Tuba1a

Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0000226 microtubule cytoskeleton organization	IBA GO_REF:0000033	ACCEPT	Summary: Alpha-tubulin is a core structural component of microtubules, and its role in microtubule cytoskeleton organization is well established across the tubulin family. Tuba1a S140G mutant mice show disrupted microtubule organization in the brain (PMID:17218254, PMID:28687665). Reason: Core function of alpha-tubulin. Mutations in Tuba1a directly impair microtubule cytoskeleton organization as demonstrated in multiple ENU mutant mouse studies. Supporting Evidence: PMID:17218254 the causative mutation lies in the guanosine triphosphate (GTP) binding pocket of alpha-1 tubulin (Tuba1) and affects tubulin heterodimer formation PMID:28687665 Tuba1a mutation led to increased straightness of newly polymerized MTs file:mouse/Tuba1a/Tuba1a-deep-research-falcon.md Mouse Tuba1a encodes a neuronal alpha-tubulin isotype that heterodimerizes with beta-tubulin and incorporates into microtubule polymers; it is required for neurite extension, neuronal migration, and intracellular transport.
GO:0005737 cytoplasm	IBA GO_REF:0000033	ACCEPT	Summary: Alpha-tubulin is a cytoplasmic protein that forms microtubules in the cytoplasm. This is a fundamental localization for all tubulins. Reason: Core localization for alpha-tubulin. Well established across all tubulin family members.
GO:0005874 microtubule	IBA GO_REF:0000033	ACCEPT	Summary: Alpha-tubulin is a structural component of microtubules, forming alpha/beta heterodimers that polymerize into the microtubule lattice. This is a core localization for Tuba1a. Reason: Core localization. Alpha-tubulin is literally a building block of microtubules. UniProt confirms this is a major constituent of microtubules. Supporting Evidence: PMID:17218254 a FLAG-tagged mutant Tuba1 incorporated into the normal interphase microtubule network upon overexperession in cultured cells
GO:0000278 mitotic cell cycle	IBA GO_REF:0000033	KEEP AS NON CORE	Summary: Alpha-tubulin is required for mitotic spindle formation during cell division. This is a conserved function across the tubulin family. Reason: While microtubules are essential for mitotic spindle function, Tuba1a is primarily expressed in post-mitotic neurons (PMID:26658218). Other alpha-tubulin isotypes (e.g. Tuba1b, Tuba1c) are more likely the primary contributors to the mitotic spindle in dividing cells. Valid IBA annotation but not a core function of Tuba1a specifically.
GO:0005200 structural constituent of cytoskeleton	IBA GO_REF:0000033	ACCEPT	Summary: Alpha-tubulin is a core structural constituent of the microtubule cytoskeleton. This is the primary molecular function of alpha-tubulin. Reason: This is the defining molecular function of alpha-tubulin. UniProt annotates it with EC 3.6.5.- and describes it as "the major constituent of microtubules."
GO:0030182 neuron differentiation	IBA GO_REF:0000033	KEEP AS NON CORE	Summary: Tuba1a plays a key role in neuron differentiation through its requirement for neuronal migration and morphogenesis. Multiple Tuba1a mutant mice show defects in neuronal development (PMID:17218254, PMID:28687665, PMID:26658218). Reason: Tuba1a is the predominant alpha-tubulin in post-mitotic neurons and is essential for neuronal morphogenesis, but the direct supported process is neuronal migration and microtubule-dependent neurite extension rather than differentiation fate specification. Supporting Evidence: PMID:26658218 Tuba1a is highly expressed in the brain during late embryonic development, and specifically enriched in post-mitotic neurons that extend long processes
GO:0005525 GTP binding	IBA GO_REF:0000033	ACCEPT	Summary: Alpha-tubulin binds GTP at the non-exchangeable N-site, which acts as a structural cofactor stabilizing the alpha/beta heterodimer. This is a fundamental property of all alpha-tubulins. Reason: Core molecular function. GTP binding is essential for tubulin heterodimer stability and microtubule polymerization. The Jenna (S140G) mutation directly affects GTP binding at the N-site (PMID:17218254). Supporting Evidence: PMID:17218254 The mutation causes an amino acid change from serine to glycine at residue 140 (S140G)
GO:0005200 structural constituent of cytoskeleton	IEA GO_REF:0000002	ACCEPT	Summary: IEA annotation consistent with IBA annotation for the same term. Structural constituent of cytoskeleton is the core molecular function of alpha-tubulin. Reason: Redundant with IBA annotation but correctly assigned. Core function.
GO:0005525 GTP binding	IEA GO_REF:0000002	ACCEPT	Summary: IEA annotation consistent with IBA annotation for the same term. GTP binding is essential for tubulin function. Reason: Redundant with IBA annotation but correctly assigned. Core function.
GO:0005856 cytoskeleton	IEA GO_REF:0000044	ACCEPT	Summary: Tubulin is a component of the cytoskeleton. This is a broader parent term of microtubule cytoskeleton. Reason: Correct but less specific than microtubule cytoskeleton (GO:0015630). Acceptable as a broader IEA term.
GO:0005874 microtubule	IEA GO_REF:0000120	ACCEPT	Summary: IEA annotation consistent with IBA annotation. Alpha-tubulin is a component of microtubules. Reason: Redundant with IBA annotation but correctly assigned. Core localization.
GO:0007017 microtubule-based process	IEA GO_REF:0000002	ACCEPT	Summary: Alpha-tubulin is involved in microtubule-based processes. This is a broad parent term. Reason: Correct but very broad. Acceptable as an IEA annotation since more specific terms are also present.
GO:0005515 protein binding	IPI PMID:19893491 CYLD negatively regulates cell-cycle progression by inactiva...	MARK AS OVER ANNOTATED	Summary: PMID:19893491 demonstrates that CYLD interacts with alpha-tubulin through its CAP-Gly domains. The interaction was shown by co-immunoprecipitation in keratinocytes and melanocytes. However, "protein binding" is uninformative. Reason: The CYLD-alpha-tubulin interaction is experimentally supported, but GO:0005515 is an uninformative generic binding term and does not capture a core Tuba1a activity. The functional direction in the paper is CYLD binding polymerized tubulin and regulating HDAC6-mediated tubulin acetylation, not a specific binding activity that should define Tuba1a function. Supporting Evidence: PMID:19893491 Immunoprecipitation of endogenous CYLD in melanocytes revealed an interaction with alpha-tubulin
GO:0005879 axonemal microtubule	IEA GO_REF:0000107	ACCEPT	Summary: Tuba1a has been directly identified as a component of sperm flagellar doublet microtubules by cryo-ET (PMID:37865089). Axonemal microtubules are the doublet microtubules found in cilia and flagella. Reason: Directly supported by structural evidence from cryo-ET of mouse sperm flagella (PMID:37865089). Also consistent with UniProt subcellular location annotation. Supporting Evidence: PMID:37865089 in situ cryoET and subtomogram averaging has achieved up to 6.0 Å reconstructions of native microtubule structures in mouse and human sperm samples
GO:0005929 cilium	IEA GO_REF:0000107	ACCEPT	Summary: Alpha-tubulin is a component of ciliary microtubules. Consistent with the UniProt annotation showing flagellum axoneme localization and Reactome pathways for cilium assembly. Reason: Supported by the broader literature on tubulin in cilia and flagella, and by Reactome pathways (R-MMU-5617833 Cilium Assembly).
GO:0015630 microtubule cytoskeleton	IEA GO_REF:0000107	ACCEPT	Summary: Alpha-tubulin is a fundamental component of the microtubule cytoskeleton. Reason: Core localization. Well established for all alpha-tubulins.
GO:0036464 cytoplasmic ribonucleoprotein granule	IEA GO_REF:0000107	MARK AS OVER ANNOTATED	Summary: This annotation suggests Tuba1a localizes to cytoplasmic ribonucleoprotein granules. While microtubules are involved in transport and localization of RNP granules, the evidence for Tuba1a being a resident component of these granules is not strong. Reason: This is likely a high-throughput proteomics-based annotation transferred from the human ortholog. While microtubules transport RNP granules, tubulin itself is not a functional component of RNP granules; it is a component of the microtubule tracks these granules travel on.
GO:0042802 identical protein binding	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Alpha-tubulin can form lateral contacts with other alpha-tubulin subunits within the microtubule lattice. This is a consequence of its role in microtubule polymerization. Reason: While alpha-tubulin does make lateral contacts with itself in the microtubule lattice, the primary functional interaction is heterodimer formation with beta-tubulin (protein heterodimerization activity). Identical protein binding is a secondary consequence of microtubule structure, not a primary function.
GO:0055037 recycling endosome	IEA GO_REF:0000107	MARK AS OVER ANNOTATED	Summary: This annotation suggests Tuba1a localizes to recycling endosomes. This is likely from proteomics experiments where tubulin was detected in endosome-enriched fractions. Reason: Tubulin is highly abundant and can be detected in many subcellular fractions. Microtubules provide tracks for recycling endosome transport, but tubulin is not a bona fide component of the recycling endosome itself. This is a common over-annotation for abundant cytoskeletal proteins.
GO:0035371 microtubule plus-end	IMP PMID:20603323 Disease-associated mutations in TUBA1A result in a spectrum ...	ACCEPT	Summary: PMID:20603323 examined disease-associated TUBA1A mutations and showed suppression of microtubule growth rate in neurites. Newly incorporated tubulin dimers are added at the plus-end of microtubules. Reason: Alpha-tubulin is incorporated at the microtubule plus-end during polymerization. This is a well-established localization for newly assembled tubulin. Supporting Evidence: PMID:20603323 a suppression of microtubule growth rate in the neurites (but not the soma) of cultured neurons
GO:0005874 microtubule	ISO GO_REF:0000119	ACCEPT	Summary: ISO annotation for microtubule localization, consistent with IBA annotation. Core localization. Reason: Redundant with IBA but correct. Core localization.
GO:0005879 axonemal microtubule	ISO GO_REF:0000119	ACCEPT	Summary: ISO annotation for axonemal microtubule localization. Directly supported by cryo-ET of mouse sperm flagella (PMID:37865089). Reason: Correct. Directly confirmed by PMID:37865089.
GO:0005929 cilium	ISO GO_REF:0000119	ACCEPT	Summary: ISO annotation for cilium localization. Consistent with the known role of alpha-tubulin in cilia and flagella. Reason: Correct. Consistent with flagellum localization shown in PMID:37865089.
GO:0015630 microtubule cytoskeleton	ISO GO_REF:0000119	ACCEPT	Summary: ISO annotation for microtubule cytoskeleton. Core localization. Reason: Correct. Redundant with IEA but well established.
GO:0036464 cytoplasmic ribonucleoprotein granule	ISO GO_REF:0000119	MARK AS OVER ANNOTATED	Summary: ISO annotation for RNP granule localization. Same concern as the IEA annotation. Reason: Same issue as the IEA annotation. Tubulin is not a bona fide component of RNP granules. Likely an artifact of proteomic co-purification due to tubulin abundance.
GO:0042802 identical protein binding	ISO GO_REF:0000119	KEEP AS NON CORE	Summary: ISO annotation for identical protein binding. Same assessment as the IEA annotation. Reason: Technically true due to lateral contacts in the microtubule lattice, but not a primary functional activity. The core interaction is heterodimerization with beta-tubulin.
GO:0055037 recycling endosome	ISO GO_REF:0000119	MARK AS OVER ANNOTATED	Summary: ISO annotation for recycling endosome localization. Same concern as the IEA annotation. Reason: Tubulin is not a resident component of recycling endosomes. Likely over-annotation from proteomics data.
GO:0019904 protein domain specific binding	ISO GO_REF:0000096	KEEP AS NON CORE	Summary: This annotation suggests Tuba1a has protein domain specific binding activity. Alpha-tubulin interacts with various MAPs and motors through specific domain interactions. Reason: Alpha-tubulin does interact with specific protein domains (e.g., CAP-Gly domains of CYLD, CLIP proteins), but this is a generic term. Not a core molecular function annotation.
GO:0043209 myelin sheath	ISO GO_REF:0000096	KEEP AS NON CORE	Summary: ISO annotation for myelin sheath localization. Consistent with the HDA annotation from PMID:17634366 showing tubulin in purified myelin membranes. Reason: Tubulin has been detected in myelin proteomics studies (PMID:17634366), but this likely reflects cytoskeletal contamination of myelin preparations or microtubule tracks within myelin-forming oligodendrocyte processes. Not a core localization.
GO:0045121 membrane raft	ISO GO_REF:0000096	MARK AS OVER ANNOTATED	Summary: This annotation suggests Tuba1a localizes to membrane rafts. Tubulin has been detected in detergent-resistant membrane fractions in some proteomics studies. Reason: Tubulin is one of the most abundant cellular proteins and is frequently detected in membrane raft preparations. This likely represents non-specific association or contamination rather than bona fide localization to membrane rafts.
GO:0030317 flagellated sperm motility	IDA PMID:37865089 De novo protein identification in mammalian sperm using in s...	KEEP AS NON CORE	Summary: PMID:37865089 identified Tuba1a as a component of sperm flagellar doublet microtubules using cryo-ET and AlphaFold2 docking. Tubulin is essential for flagellar assembly and motility. Reason: Tuba1a is a component of sperm flagellar microtubules, but its role in sperm motility is as a structural component rather than a regulatory one. This is a non-core function compared to its primary neuronal roles. The annotation is valid but represents a secondary tissue-specific function. Supporting Evidence: PMID:37865089 in situ cryoET and subtomogram averaging has achieved up to 6.0 Å reconstructions of native microtubule structures in mouse and human sperm samples
GO:0036126 sperm flagellum	IDA PMID:37865089 De novo protein identification in mammalian sperm using in s...	ACCEPT	Summary: PMID:37865089 directly identified Tuba1a in sperm flagellar doublet microtubules by cryo-ET structure determination at 7.7 angstrom resolution. Reason: Directly demonstrated by structural biology (cryo-ET). Tuba1a is a component of sperm flagellar doublet microtubules. Supporting Evidence: PMID:37865089 in situ cryoET and subtomogram averaging has achieved up to 6.0 Å reconstructions of native microtubule structures in mouse and human sperm samples
GO:0031594 neuromuscular junction	IMP PMID:26658218 Novel α-tubulin mutation disrupts neural development and tub...	KEEP AS NON CORE	Summary: PMID:26658218 showed that Tuba1a mutant mice (ND allele) have motor neuron synapse defects at the neuromuscular junction. Homozygous mutants showed failure of motor neurons to innervate target muscles. Reason: Tuba1a is localized to the NMJ as part of the microtubule cytoskeleton in motor neuron axon terminals. The defects in NMJ are secondary to its role in microtubule-based transport and synapse maintenance. Supporting Evidence: PMID:26658218 Motor neurons fail to innervate target muscles in the limbs and show synapse defects at proximal targets
GO:0031594 neuromuscular junction	IDA PMID:26658218 Novel α-tubulin mutation disrupts neural development and tub...	KEEP AS NON CORE	Summary: IDA annotation indicating Tuba1a is detected at the neuromuscular junction. This is consistent with the IMP annotation from the same paper. Reason: Tuba1a is present at the NMJ as part of the microtubule cytoskeleton but this is a secondary localization. Supporting Evidence: PMID:26658218 Motor neurons fail to innervate target muscles in the limbs and show synapse defects at proximal targets
GO:0050807 regulation of synapse organization	IMP PMID:26658218 Novel α-tubulin mutation disrupts neural development and tub...	KEEP AS NON CORE	Summary: PMID:26658218 demonstrated that Tuba1a ND mutation leads to synapse defects at the NMJ. The study also showed NMJ size reduction over time in heterozygous mutants (PMID:32184299). Reason: Tuba1a contributes to synapse organization through its role in microtubule-based transport and cytoskeletal integrity, but this is a downstream consequence rather than a direct regulatory function. The synapse defects are secondary to general microtubule dysfunction. Supporting Evidence: PMID:26658218 Motor neurons fail to innervate target muscles in the limbs and show synapse defects at proximal targets
GO:0050807 regulation of synapse organization	IDA PMID:26658218 Novel α-tubulin mutation disrupts neural development and tub...	KEEP AS NON CORE	Summary: IDA annotation for regulation of synapse organization from the same paper as the IMP annotation. Reason: Same rationale as the IMP annotation. Synapse organization effects are secondary to microtubule dysfunction.
GO:0000226 microtubule cytoskeleton organization	IMP PMID:22101068 Behavioral and neuromorphological characterization of a nove...	ACCEPT	Summary: PMID:22101068 describes a novel ENU-induced Tuba1a mutant (D263G) with abnormal brain morphology indicating disrupted microtubule organization during development. Reason: Core function. The D263G mutation in Tuba1a disrupts microtubule cytoskeleton organization, consistent with the S140G allele (PMID:17218254). Supporting Evidence: PMID:22101068 We identified a missense mutation in the Tuba1 gene, which encodes the TUBA1 protein, and designated the mutant gene Tuba1(Rgsc1736). This mutation results in an aspartic acid to glycine substitution in the TUBA1 protein.
GO:0007626 locomotory behavior	IMP PMID:22101068 Behavioral and neuromorphological characterization of a nove...	KEEP AS NON CORE	Summary: PMID:22101068 showed the Tuba1a Rgsc1736 mutant has significantly increased spontaneous locomotor activity, consistent with the hyperactive Jenna mutant (PMID:17218254). Reason: Locomotory behavior defects are downstream consequences of impaired neuronal migration and brain malformation, not a direct function of Tuba1a. This is a phenotypic readout of Tuba1a mutation rather than a function. Supporting Evidence: PMID:22101068 exhibited a significant increase in spontaneous locomotor activity
GO:0021859 pyramidal neuron differentiation	IMP PMID:22101068 Behavioral and neuromorphological characterization of a nove...	KEEP AS NON CORE	Summary: PMID:22101068 and PMID:17218254 both show disrupted pyramidal cell layers in the hippocampus of Tuba1a mutant mice, indicating a role in pyramidal neuron differentiation. Reason: The pyramidal neuron phenotype is a consequence of impaired neuronal migration rather than a specific role in pyramidal neuron differentiation per se. The defect is in migration not differentiation fate determination. Supporting Evidence: PMID:17218254 Staining with cresyl violet and with the neuronal marker NeuN showed hippocampal disorganization with an additional layer of pyramidal cells in the stratum oriens
GO:0021987 cerebral cortex development	IMP PMID:22101068 Behavioral and neuromorphological characterization of a nove...	KEEP AS NON CORE	Summary: PMID:22101068 showed cortical abnormalities in the Tuba1a Rgsc1736 mutant. PMID:17218254 showed wave-like perturbations in cortical layers II/III and IV in the Jenna mutant. Reason: Cerebral cortex development is affected by Tuba1a mutations, but this is a downstream phenotypic consequence of impaired neuronal migration. The core function is microtubule-based neuronal migration, which then impacts cortical development. Supporting Evidence: PMID:17218254 closer examination of NeuN, Cux-1, and Nissl stains revealed wave-like perturbations in layer IV
GO:0035641 locomotory exploration behavior	IMP PMID:22101068 Behavioral and neuromorphological characterization of a nove...	KEEP AS NON CORE	Summary: PMID:22101068 showed the mutant exhibited abnormal open-field behavior and inattention to novel objects, which relates to locomotory exploration. Reason: Behavioral phenotype is a distal consequence of brain malformation caused by Tuba1a mutation. Not a direct function. Supporting Evidence: PMID:22101068 Tuba1(Rgsc1736) heterozygotes exhibited inattention to novel objects and aberrant patterns of home-cage activity
GO:0006886 intracellular protein transport	IMP PMID:32184299 Reduced TUBA1A Tubulin Causes Defects in Trafficking and Imp...	KEEP AS NON CORE	Summary: PMID:32184299 showed that reduced TUBA1A results in fewer microtubule tracks in axons, leading to more pausing during organelle trafficking. Trafficking defects impair synaptic maintenance. Reason: Tuba1a contributes to intracellular transport by providing microtubule tracks for motor protein-based transport. The trafficking defect is secondary to reduced microtubule assembly. This is a downstream consequence of Tuba1a's structural role. Supporting Evidence: PMID:32184299 reduced TUBA1A allows for assembly of less microtubules in axons resulting in more pausing during organelle trafficking
GO:0046785 microtubule polymerization	IMP PMID:32184299 Reduced TUBA1A Tubulin Causes Defects in Trafficking and Imp...	ACCEPT	Summary: PMID:32184299 showed reduced microtubule assembly in axons of Tuba1a ND mutant neurons. Alpha-tubulin is the building block for microtubule polymerization. Reason: Core function. Alpha-tubulin heterodimers are the direct subunits that polymerize to form microtubules. Reduced Tuba1a leads directly to fewer microtubules. Supporting Evidence: PMID:32184299 reduced TUBA1A allows for assembly of less microtubules in axons
GO:0050808 synapse organization	IMP PMID:32184299 Reduced TUBA1A Tubulin Causes Defects in Trafficking and Imp...	KEEP AS NON CORE	Summary: PMID:32184299 showed Tuba1a ND heterozygous mice develop age-related NMJ synapse size reduction, demonstrating a role in synapse maintenance/organization. Reason: Synapse organization defects are downstream of microtubule-based transport deficits. The NMJ synapse deterioration is secondary to reduced microtubule tracks for trafficking. Supporting Evidence: PMID:32184299 However, NMJ synapse morphology and animal behavior deteriorate in an age-related manner in Tuba1aND/+animals, without evidence of neuronal cell death or degeneration
GO:0061744 motor behavior	IMP PMID:32184299 Reduced TUBA1A Tubulin Causes Defects in Trafficking and Imp...	KEEP AS NON CORE	Summary: PMID:32184299 showed Tuba1a ND heterozygous mice develop adult-onset ataxia. Motor behavior deficits are a phenotypic consequence of synaptic and trafficking defects. Reason: Motor behavior deficits are a distal phenotypic consequence of Tuba1a mutation, not a direct function. Behavioral phenotypes should be kept as non-core. Supporting Evidence: PMID:32184299 Tuba1aND/+ mice develop adult-onset ataxia
GO:0072384 organelle transport along microtubule	IMP PMID:32184299 Reduced TUBA1A Tubulin Causes Defects in Trafficking and Imp...	KEEP AS NON CORE	Summary: PMID:32184299 showed trafficking defects with more pausing during organelle transport in Tuba1a ND neurons due to insufficient microtubule tracks. Reason: Tuba1a provides the microtubule tracks for organelle transport. The transport defects are secondary to reduced microtubule assembly. Not a direct function of Tuba1a but a consequence of its structural role. Supporting Evidence: PMID:32184299 reduced TUBA1A allows for assembly of less microtubules in axons resulting in more pausing during organelle trafficking
GO:0000226 microtubule cytoskeleton organization	IMP PMID:28687665 Mutation of the α-tubulin Tuba1a leads to straighter microtu...	ACCEPT	Summary: PMID:28687665 showed the S140G mutation leads to increased straightness of newly polymerized microtubules and altered conformational properties of the alpha/beta heterodimer. Reason: Core function. Directly demonstrates the role of Tuba1a in microtubule cytoskeleton organization through its effect on microtubule geometry and dynamics. Supporting Evidence: PMID:28687665 Tuba1a mutation led to increased straightness of newly polymerized MTs, and structural modeling data suggest a conformational change in the alpha/beta-tubulin heterodimer
GO:0001764 neuron migration	IMP PMID:28687665 Mutation of the α-tubulin Tuba1a leads to straighter microtu...	ACCEPT	Summary: PMID:28687665 showed slowed neuronal migration and increased branching in Tuba1a S140G mutant neurons by live imaging. Neurons accumulated along the rostral migratory stream. Reason: Core function. Neuron migration is the most well-established and specific phenotype of Tuba1a mutations across multiple independent alleles and studies. This is the defining function of Tuba1a in brain development. Supporting Evidence: PMID:28687665 Live imaging of Tuba1a-mutant neurons revealed slowed migration and increased neuronal branching, which correlated with directionality alterations and perturbed nucleus-centrosome (N-C) coupling
GO:0001764 neuron migration	IMP PMID:31386652 Differential requirements of tubulin genes in mammalian fore...	ACCEPT	Summary: PMID:31386652 generated Tuba1a knockout mice and showed perinatal lethality with significant forebrain dysmorphology due to migration defects. Reason: Core function. The null allele confirms the essential, non-redundant role of Tuba1a in neuronal migration. Supporting Evidence: PMID:31386652 loss of Tuba1a is perinatal lethal and leads to significant forebrain dysmorphology
GO:0007098 centrosome cycle	IMP PMID:28687665 Mutation of the α-tubulin Tuba1a leads to straighter microtu...	KEEP AS NON CORE	Summary: PMID:28687665 showed perturbed nucleus-centrosome coupling in Tuba1a S140G mutant neurons, which is relevant to the centrosome cycle during neuronal migration. Reason: The centrosome coupling defect is a consequence of altered microtubule properties rather than a direct role in centrosome cycle regulation. The annotation is somewhat overspecific. Supporting Evidence: PMID:28687665 perturbed nucleus-centrosome (N-C) coupling
GO:0010001 glial cell differentiation	IMP PMID:28687665 Mutation of the α-tubulin Tuba1a leads to straighter microtu...	KEEP AS NON CORE	Summary: PMID:28687665 showed that glial cells are dispersed along the rostral migratory stream in Tuba1a S140G mutants. Reason: The glial cell dispersion is likely secondary to disrupted migration rather than a specific role in glial cell differentiation. Microtubules are broadly required in all cell types. Supporting Evidence: PMID:28687665 glial cells are dispersed along the rostral migratory stream in postnatal and adult brains
GO:0010467 gene expression	IMP PMID:31386652 Differential requirements of tubulin genes in mammalian fore...	MARK AS OVER ANNOTATED	Summary: PMID:31386652 examined differential requirements of tubulin genes in forebrain development. The annotation to gene expression is very broad and likely relates to indirect effects of Tuba1a loss on downstream gene expression patterns. Reason: Gene expression is an extremely broad term. Tuba1a is not a transcription factor or transcriptional regulator. Any effects on gene expression are indirect, downstream consequences of disrupted microtubule-dependent signaling or altered cellular state due to loss of Tuba1a. This is over-annotation.
GO:0021987 cerebral cortex development	IMP PMID:31386652 Differential requirements of tubulin genes in mammalian fore...	KEEP AS NON CORE	Summary: PMID:31386652 showed Tuba1a null mice have significant forebrain dysmorphology. Also shown in multiple other Tuba1a mutant studies. Reason: Valid phenotype but cerebral cortex development is a downstream consequence of Tuba1a's role in neuronal migration. Keep as non-core. Supporting Evidence: PMID:31386652 loss of Tuba1a is perinatal lethal and leads to significant forebrain dysmorphology
GO:0022008 neurogenesis	IMP PMID:31386652 Differential requirements of tubulin genes in mammalian fore...	KEEP AS NON CORE	Summary: PMID:31386652 showed defects in forebrain neurogenesis in Tuba1a null mice. Consistent with the essential role in neuronal development. Reason: Neurogenesis is a broad parent term. The specific function of Tuba1a is in neuron migration rather than neurogenesis per se. The neurogenesis annotation from PMID:21041996 showed normal neurogenic potential but ectopic positioning, confirming that the problem is migration, not generation of neurons. Supporting Evidence: PMID:21041996 mice harbouring an S140G mutation in Tuba1a present with normal neurogenic potential, but that this neurogenesis is often ectopic
GO:0030182 neuron differentiation	IMP PMID:28687665 Mutation of the α-tubulin Tuba1a leads to straighter microtu...	KEEP AS NON CORE	Summary: PMID:28687665 showed defects in neuronal migration and branching in Tuba1a S140G mutant, which affects neuron differentiation. Reason: The evidence supports altered migration and branching in mutant neurons. This is consistent with neuronal morphogenesis but is broader than the most precise supported process, neuron migration, so it should be retained as non-core. Supporting Evidence: PMID:28687665 our work shows that Tuba1a plays an essential, noncompensated role in neuronal saltatory migration in vivo
GO:0046785 microtubule polymerization	IMP PMID:28687665 Mutation of the α-tubulin Tuba1a leads to straighter microtu...	ACCEPT	Summary: PMID:28687665 showed altered microtubule polymerization properties (increased straightness) in Tuba1a S140G mutant neurons. Reason: Core function. Tuba1a heterodimers are the building blocks for microtubule polymerization. The S140G mutation directly alters polymerization properties. Supporting Evidence: PMID:28687665 Tuba1a mutation led to increased straightness of newly polymerized MTs
GO:0048853 forebrain morphogenesis	IMP PMID:31386652 Differential requirements of tubulin genes in mammalian fore...	KEEP AS NON CORE	Summary: PMID:31386652 showed Tuba1a null mice have significant forebrain dysmorphology with perinatal lethality. Reason: Forebrain morphogenesis defects are a downstream consequence of impaired neuronal migration. Keep as non-core. Supporting Evidence: PMID:31386652 loss of Tuba1a is perinatal lethal and leads to significant forebrain dysmorphology
GO:0140058 neuron projection arborization	IMP PMID:28687665 Mutation of the α-tubulin Tuba1a leads to straighter microtu...	KEEP AS NON CORE	Summary: PMID:28687665 showed increased neuronal branching in Tuba1a S140G mutant neurons during migration by live imaging. Reason: Increased branching is observed in Tuba1a mutant neurons but this reflects altered microtubule dynamics rather than a direct role in arborization regulation. Keep as non-core. Supporting Evidence: PMID:28687665 Live imaging of Tuba1a-mutant neurons revealed slowed migration and increased neuronal branching
GO:0001764 neuron migration	IMP PMID:21041996 The role of Tuba1a in adult hippocampal neurogenesis and the...	ACCEPT	Summary: PMID:21041996 showed that S140G mutant mice have defective migration of neurons in the dentate gyrus, with normal neurogenic potential but ectopic positioning. Reason: Core function. This study specifically demonstrated that the neurogenesis is normal but migration is defective in Tuba1a mutant hippocampus. Supporting Evidence: PMID:21041996 mice harbouring an S140G mutation in Tuba1a present with normal neurogenic potential, but that this neurogenesis is often ectopic. Morphological analysis of the dentate gyrus in adulthood revealed a disorganised subgranular zone and a dispersed granule cell layer.
GO:0007224 smoothened signaling pathway	IDA PMID:27793670 Ciliary smoothened-mediated noncanonical hedgehog signaling ...	MARK AS OVER ANNOTATED	Summary: PMID:27793670 showed that Hh pathway activation increases microtubule acetylation via Smoothened in MEFs. Tubulin acetylation is a downstream readout, not an active participant in Smo signaling. Reason: Tuba1a is a substrate of acetylation downstream of Smo signaling, not an active participant in the smoothened signaling pathway. The study shows that Smo promotes tubulin acetylation, meaning tubulin is a downstream target/substrate, not a signaling component. This is over-annotation. Supporting Evidence: PMID:27793670 Hh pathway activation in mouse embryonic fibroblast cells (MEFs) increases microtubule acetylation via smoothened (Smo)
GO:0071277 cellular response to calcium ion	IDA PMID:27793670 Ciliary smoothened-mediated noncanonical hedgehog signaling ...	MARK AS OVER ANNOTATED	Summary: PMID:27793670 showed that intracellular calcium increase is important for Hh-dependent tubulin acetylation downstream of Smo. Again, tubulin is a downstream substrate modified in response to calcium. Reason: Tubulin acetylation occurs in response to calcium signaling downstream of Smo, but tubulin itself is not responding to calcium in any direct sense. It is a substrate that gets modified. This is over-annotation of a passive substrate. Supporting Evidence: PMID:27793670 an increase in intracellular calcium is important for Hh-dependent tubulin acetylation at the downstream of Smo
GO:0009612 response to mechanical stimulus	IMP PMID:27976998 Acetylated tubulin is essential for touch sensation in mice.	KEEP AS NON CORE	Summary: PMID:27976998 showed that mice lacking Atat1 (the alpha-tubulin acetyltransferase) in sensory neurons have profound deficits in mechanosensitivity. Acetylated tubulin at K40 is essential for touch sensation by maintaining cellular stiffness. Reason: The study demonstrates that tubulin acetylation (which occurs on alpha-tubulin K40) is essential for mechanosensitivity. However, the annotation is to Tuba1a specifically when the study used Atat1 knockout mice. The mechanosensitivity role is for acetylated alpha-tubulin generally, not Tuba1a specifically. Keep as non-core since alpha-tubulin acetylation is important for touch but may involve multiple alpha-tubulin isotypes. Supporting Evidence: PMID:27976998 mice lacking the alpha-tubulin acetyltransferase Atat1 in sensory neurons display profound deficits in their ability to detect mechanical stimuli
GO:0021542 dentate gyrus development	IMP PMID:21041996 The role of Tuba1a in adult hippocampal neurogenesis and the...	KEEP AS NON CORE	Summary: PMID:21041996 showed the Tuba1a S140G mutant has a disorganized subgranular zone and dispersed granule cell layer in the dentate gyrus due to defective migration. Reason: Dentate gyrus development defects are a downstream consequence of impaired neuronal migration in the hippocampus. Keep as non-core. Supporting Evidence: PMID:21041996 Morphological analysis of the dentate gyrus in adulthood revealed a disorganised subgranular zone and a dispersed granule cell layer
GO:0022008 neurogenesis	IMP PMID:21041996 The role of Tuba1a in adult hippocampal neurogenesis and the...	KEEP AS NON CORE	Summary: PMID:21041996 explicitly showed normal neurogenic potential but ectopic neurogenesis in Tuba1a mutant mice. Reason: The study showed neurogenic potential is normal but positioning is ectopic. The core function is migration, not neurogenesis. This annotation should be kept as non-core since the defect is in migration of newly generated neurons, not in neurogenesis itself. Supporting Evidence: PMID:21041996 mice harbouring an S140G mutation in Tuba1a present with normal neurogenic potential, but that this neurogenesis is often ectopic
GO:0000226 microtubule cytoskeleton organization	IMP PMID:21875651 Cytoarchitectural disruption of the superior colliculus and ...	ACCEPT	Summary: PMID:21875651 showed that the S140G mutation impairs radial migration of neurons in the superior colliculus, leading to thinning and apparent layer fusion due to microtubule dysfunction. Reason: Core function. Consistent with the IBA and other IMP annotations for microtubule cytoskeleton organization. Supporting Evidence: PMID:21875651 The Jenna mutant mouse harbours an S140G mutation in Tuba1a that impairs tubulin heterodimer formation resulting in defective neuronal migration during development
GO:0000793 condensed chromosome	IDA PMID:24244602 TFIIB co-localizes and interacts with α-tubulin during oocyt...	KEEP AS NON CORE	Summary: PMID:24244602 showed TFIIB co-localizes with alpha-tubulin on condensed chromosomes during oocyte meiosis. Alpha-tubulin is part of the spindle that interacts with condensed chromosomes. Reason: The study primarily concerns TFIIB localization. Alpha-tubulin is present at the spindle near condensed chromosomes during meiosis, but is not a component of the condensed chromosome itself. The annotation may be slightly misleading but reflects the mitotic spindle-chromosome interface. Keep as non-core. Supporting Evidence: PMID:24244602 After progression to GV breakdown (GVBD), TFIIB and alpha-tubulin co-localize and accumulate in the vicinity of the condensed chromosomes
GO:0001764 neuron migration	IMP PMID:21875651 Cytoarchitectural disruption of the superior colliculus and ...	ACCEPT	Summary: PMID:21875651 showed impaired radial migration of neurons in the superior colliculus of S140G mutant mice using birthdate labeling at E12.5 and E13.5. Reason: Core function. Neuron migration defects in the superior colliculus add to the body of evidence across cortex, hippocampus, and RMS that Tuba1a is essential for neuronal migration. Supporting Evidence: PMID:21875651 the S140G mutation impairs the radial migration of neurons in the SC
GO:0001964 startle response	IMP PMID:21875651 Cytoarchitectural disruption of the superior colliculus and ...	KEEP AS NON CORE	Summary: PMID:21875651 showed Tuba1a S140G mutant mice have an exaggerated acoustic startle response, consistent with disrupted superior colliculus cytoarchitecture. Reason: The startle response phenotype is a distal behavioral consequence of disrupted brain cytoarchitecture due to impaired neuronal migration. Not a direct function. Supporting Evidence: PMID:21875651 we find that Jenna mutants exhibit an exaggerated acoustic startle response
GO:0005515 protein binding	IPI PMID:24244602 TFIIB co-localizes and interacts with α-tubulin during oocyt...	MARK AS OVER ANNOTATED	Summary: PMID:24244602 showed TFIIB interacts with alpha-tubulin by BiFC and co-localization during oocyte meiosis. Reason: The TFIIB-alpha-tubulin interaction is supported, but GO:0005515 is too generic to be informative for Tuba1a. The paper primarily supports TFIIB association with spindle microtubules during oocyte meiosis; it does not establish a distinct Tuba1a binding function beyond its microtubule structural role. Supporting Evidence: PMID:24244602 co-transfection of BiFC plasmids pHA-Tf2b and pFlag-Tuba1alpha further confirms a direct interaction between TFIIB and alpha-tubulins
GO:0048873 homeostasis of number of cells within a tissue	IMP PMID:21875651 Cytoarchitectural disruption of the superior colliculus and ...	KEEP AS NON CORE	Summary: PMID:21875651 showed a massive reduction in postmitotic neurons in the superior colliculus of Tuba1a mutant mice in adulthood, attributed to increased apoptotic cell death. Reason: The neuronal cell number reduction is a downstream consequence of impaired migration and subsequent apoptosis. Tuba1a does not directly regulate cell number homeostasis. Supporting Evidence: PMID:21875651 A quantitative assessment of neuronal number in adulthood reveals a massive reduction in postmitotic neurons in mutant animals, which we attribute to increased apoptotic cell death
GO:0051402 neuron apoptotic process	IMP PMID:21875651 Cytoarchitectural disruption of the superior colliculus and ...	KEEP AS NON CORE	Summary: PMID:21875651 showed increased apoptotic cell death in the superior colliculus of Tuba1a S140G mutant mice leading to neuronal loss. Reason: Neuronal apoptosis is a secondary consequence of impaired migration and mispositioning, not a direct function of Tuba1a. The apoptosis likely results from failure of migrating neurons to reach proper targets. Supporting Evidence: PMID:21875651 an elevated rate of cell death leads to a significant loss of neurons in the SC of the Jna/+ mouse between postnatal day 21 (P21) and 12 weeks of age
GO:0005515 protein binding	IPI PMID:20603323 Disease-associated mutations in TUBA1A result in a spectrum ...	MODIFY	Summary: PMID:20603323 examined disease-associated TUBA1A mutations and their effects on protein interactions in the tubulin folding pathway, including interactions with prefoldin, CCT, and TBCB. Reason: Protein binding is uninformative. The specific interactions described are with chaperones (prefoldin, CCT) and tubulin-specific cofactors (TBCB) in the folding pathway. A more specific term would be protein-folding chaperone binding, which is already annotated. Proposed replacements: protein-folding chaperone binding Supporting Evidence: PMID:20603323 These include a defective interaction with the chaperone prefoldin, a reduced efficiency in the generation of productive folding intermediates as a result of inefficient interaction with the cytosolic chaperonin, CCT
GO:0006458 'de novo' protein folding	IMP PMID:20603323 Disease-associated mutations in TUBA1A result in a spectrum ...	KEEP AS NON CORE	Summary: PMID:20603323 showed that TUBA1A mutations affect the de novo tubulin folding and heterodimer assembly pathway involving CCT, prefoldin, and tubulin-specific chaperones TBCA-TBCE. Reason: Tuba1a is a substrate of the de novo folding pathway, not an active participant in the folding process. The folding is performed by chaperones (CCT, prefoldin) and tubulin cofactors (TBCA-TBCE). This annotation describes the folding of Tuba1a, not a folding activity by Tuba1a. Supporting Evidence: PMID:20603323 We show that the expression of all the mutant proteins in vitro results in the generation of tubulin heterodimers in varying yield
GO:0008017 microtubule binding	IMP PMID:20603323 Disease-associated mutations in TUBA1A result in a spectrum ...	ACCEPT	Summary: PMID:20603323 showed that once folded, mutant tubulin heterodimers can co-polymerize with microtubules in vitro, demonstrating microtubule binding activity. Reason: Alpha-tubulin heterodimers bind to existing microtubules during polymerization. This is a core molecular function. Supporting Evidence: PMID:20603323 the expression of all the mutant proteins in vitro results in the generation of tubulin heterodimers in varying yield and that these can co-polymerize with microtubules in vitro
GO:0046982 protein heterodimerization activity	IMP PMID:20603323 Disease-associated mutations in TUBA1A result in a spectrum ...	ACCEPT	Summary: PMID:20603323 directly examined tubulin heterodimer formation and showed disease mutations affect the yield of alpha/beta heterodimers through the chaperone-dependent folding pathway. Reason: Core molecular function. Alpha-tubulin heterodimerizes with beta-tubulin to form the fundamental building block of microtubules. This is a defining activity of alpha-tubulin. Supporting Evidence: PMID:20603323 We show that the expression of all the mutant proteins in vitro results in the generation of tubulin heterodimers in varying yield
GO:0050821 protein stabilization	IMP PMID:20603323 Disease-associated mutations in TUBA1A result in a spectrum ...	KEEP AS NON CORE	Summary: PMID:20603323 showed that some mutations cause structural instability in vitro and diminished stability in vivo. Tuba1a contributes to the stability of the tubulin heterodimer. Reason: The protein stabilization annotation likely refers to the role of GTP binding in stabilizing the heterodimer. This is not an active stabilization activity but rather a consequence of heterodimer formation. Keep as non-core. Supporting Evidence: PMID:20603323 Other defects include structural instability in vitro, diminished stability in vivo
GO:0051087 protein-folding chaperone binding	IDA PMID:20603323 Disease-associated mutations in TUBA1A result in a spectrum ...	KEEP AS NON CORE	Summary: PMID:20603323 showed direct interactions between TUBA1A and chaperones (prefoldin, CCT) and tubulin cofactors (TBCB) using in vitro folding assays. Reason: Tuba1a interacts with prefoldin, CCT, and tubulin-specific cofactors during maturation, and the annotation is valid. It is a biogenesis interaction required to produce folded alpha/beta heterodimers rather than the core activity of the mature gene product. Supporting Evidence: PMID:20603323 These include a defective interaction with the chaperone prefoldin, a reduced efficiency in the generation of productive folding intermediates as a result of inefficient interaction with the cytosolic chaperonin, CCT, and, in several cases, a failure to stably interact with TBCB
GO:0001764 neuron migration	IMP PMID:17218254 Mutations in alpha-tubulin cause abnormal neuronal migration...	ACCEPT	Summary: The foundational paper demonstrating that the Tuba1a S140G mutation causes impaired neuronal migration in mice and lissencephaly in humans. BrdU labeling showed defective radial migration at E14.5 and E16.5. Reason: Core function. This is the seminal paper establishing that Tuba1a is essential for neuronal migration. The migration defect was directly demonstrated by BrdU birth-dating experiments and confirmed by BAC transgene rescue. Supporting Evidence: PMID:17218254 There was no significant difference between littermate controls and Jna/+ mutants when BrdU was injected at E12.5 (F[9,189] < 1; P > 0.05), however there was a highly significant difference when injected at E14.5 (F[9,198] = 4.75; P < 0.0001), and at E16.5 (F[9,270] = 13.3; P < 0.0001)
GO:0005515 protein binding	IPI PMID:20037577 HDAC1 nuclear export induced by pathological conditions is e...	MARK AS OVER ANNOTATED	Summary: PMID:20037577 showed that HDAC1 nuclear export leads to interaction with motor proteins and impaired mitochondrial transport. The connection to alpha-tubulin is indirect -- HDAC1 interacts with tubulin-dependent motor proteins. Reason: The study identifies alpha-tubulin in pathological HDAC1/motor-protein complexes during axonal damage, but GO:0005515 is too generic and the finding is context-dependent rather than a core Tuba1a activity. The more informative biology is impaired microtubule-based mitochondrial transport under injury conditions. Supporting Evidence: PMID:20037577 The formation of complexes between exported HDAC1 and members of the kinesin family of motor proteins hindered the interaction with cargo molecules
GO:0005525 GTP binding	IMP PMID:17218254 Mutations in alpha-tubulin cause abnormal neuronal migration...	ACCEPT	Summary: PMID:17218254 directly demonstrated that the S140G mutation in the GTP binding pocket reduces GTP incorporation by approximately 5-fold using in vitro folding assays with alpha-32P-GTP. Reason: Core molecular function. Directly demonstrated by biochemical assays showing the S140G mutation in the GTP binding N-site reduces GTP binding. Supporting Evidence: PMID:17218254 We found that the S140G mutation decreased the ability of CCT bound quasi-native alpha-tubulin folding intermediates to incorporate GTP by approximately 5-fold
GO:0005829 cytosol	IDA PMID:19056362 Alpha/beta-tubulin are A kinase anchor proteins for type I P...	ACCEPT	Summary: PMID:19056362 showed tubulin forms a high molecular weight complex with PKA RI subunit mainly in the cytosol, then transported to synapses. Reason: Correct localization. Tubulin heterodimers are present in the cytosol before assembly into microtubules. Consistent with general tubulin biology. Supporting Evidence: PMID:19056362 The enrichment of the endogenous HMWC by subcellular fractionation and its synthesis in vitro indicate that it is mainly produced in the cytosol, and then transported to the synapses
GO:0005886 plasma membrane	IDA PMID:19056362 Alpha/beta-tubulin are A kinase anchor proteins for type I P...	KEEP AS NON CORE	Summary: PMID:19056362 showed PKA RI co-localized with tubulin discretely at the cell membrane in COS-7 cells. Reason: Microtubules extend to the cell periphery and interact with the plasma membrane. The plasma membrane localization detected in this study likely reflects microtubules near the membrane or tubulin-PKA complexes at the membrane. Keep as non-core since this is not the primary localization. Supporting Evidence: PMID:19056362 In mouse brain RI co-localized with tubulin in neuropils and in COS-7 cells discretely at the cell membrane
GO:0007613 memory	IMP PMID:17218254 Mutations in alpha-tubulin cause abnormal neuronal migration...	KEEP AS NON CORE	Summary: PMID:17218254 showed Tuba1a S140G mutant mice have impaired spatial working memory assessed by T-maze spontaneous and rewarded alternation. Reason: Memory deficits are a behavioral consequence of disrupted hippocampal architecture due to impaired neuronal migration. Not a direct function of Tuba1a. Supporting Evidence: PMID:17218254 Jna/+ mice performed significantly worse than littermate controls (F[1,12] = 34.1; P < 0.0001) (Figure 5A), alternating just above chance
GO:0008344 adult locomotory behavior	IMP PMID:17218254 Mutations in alpha-tubulin cause abnormal neuronal migration...	KEEP AS NON CORE	Summary: PMID:17218254 showed Tuba1a S140G mutant mice are hyperactive. BAC transgene rescue normalized locomotor behavior. Reason: Locomotor hyperactivity is a behavioral phenotype resulting from disrupted brain cytoarchitecture. Not a direct function. The rescue by BAC transgene confirms the phenotype is due to Tuba1a mutation but the behavior is a downstream readout. Supporting Evidence: PMID:17218254 A single line that we named Jenna (Jna) was identified with a semidominant hyperactive phenotype
GO:0008542 visual learning	IMP PMID:17218254 Mutations in alpha-tubulin cause abnormal neuronal migration...	REMOVE	Summary: PMID:17218254 tested visual learning-dependent reference memory. However, the Tuba1a mutant mice performed well on the visual discrimination task (tactile reference memory), showing no deficit in this hippocampal-independent task. Reason: The study actually showed that Tuba1a S140G mutants can learn a hippocampal-independent reference memory task normally. The annotation to "visual learning" appears to be an error or over-annotation, as the mutant mice showed NO deficit in this task. Supporting Evidence: PMID:17218254 Both mutant and control mice were able to learn this task (Figure 5C) (F < 1; P > 0.5)
GO:0021696 cerebellar cortex morphogenesis	IMP PMID:17218254 Mutations in alpha-tubulin cause abnormal neuronal migration...	REMOVE	Summary: PMID:17218254 stated no anatomical abnormalities were seen in the cerebellum of Jna/+ mice. Reason: The paper explicitly states no cerebellar abnormalities were seen in Jna/+ mice. This annotation appears to be an error. Supporting Evidence: PMID:17218254 No anatomical abnormalities were seen in the cerebellum or amygdala
GO:0021766 hippocampus development	IMP PMID:17218254 Mutations in alpha-tubulin cause abnormal neuronal migration...	KEEP AS NON CORE	Summary: PMID:17218254 showed extensive hippocampal disorganization in Tuba1a S140G mutant mice, including a fractured pyramidal cell layer and disorganized mossy fiber tract. Reason: Hippocampus development defects are a consequence of impaired neuronal migration. The core function is neuron migration. Keep as non-core. Supporting Evidence: PMID:17218254 hippocampal disorganization with an additional layer of pyramidal cells in the stratum oriens that extended throughout the pyramidal cell subfields into the subiculum
GO:0030534 adult behavior	IMP PMID:17218254 Mutations in alpha-tubulin cause abnormal neuronal migration...	KEEP AS NON CORE	Summary: PMID:17218254 showed multiple behavioral abnormalities including hyperactivity, impaired memory, and reduced anxiety in Tuba1a S140G mutant mice. Reason: Adult behavior is a very broad term. The behavioral phenotypes are downstream consequences of brain malformation. Keep as non-core.
GO:0034612 response to tumor necrosis factor	IDA PMID:20037577 HDAC1 nuclear export induced by pathological conditions is e...	MARK AS OVER ANNOTATED	Summary: PMID:20037577 showed that TNF-alpha treatment of neurons induces HDAC1 nuclear export and axonal damage. The study examined the effect on neurons generally, and tubulin is a component of the damaged axonal cytoskeleton. Reason: Tuba1a is not specifically responding to TNF. The study examined the effect of TNF on neurons and found HDAC1 export-dependent axonal damage. Tubulin is part of the damaged cytoskeleton but is not an active responder to TNF. This is over-annotation of a passive substrate. Supporting Evidence: PMID:20037577 cultured neurons exposed to glutamate and tumor necrosis factor-alpha
GO:0044877 protein-containing complex binding	IDA PMID:19056362 Alpha/beta-tubulin are A kinase anchor proteins for type I P...	KEEP AS NON CORE	Summary: PMID:19056362 showed alpha/beta-tubulin forms a complex with PKA RI subunit, acting as an A kinase anchor protein. This represents binding to a protein-containing complex (PKA holoenzyme). Reason: The study demonstrated that alpha/beta-tubulin can form a complex with PKA type I, serving an AKAP-like role. This is a valid but specialized signaling-complex interaction and should not be treated as the core function of Tuba1a. Supporting Evidence: PMID:19056362 we have determined that the 105 kDa band is a high molecular weight complex (HMWC) containing alpha/beta-tubulin and PKA RI
GO:0045202 synapse	IDA PMID:19056362 Alpha/beta-tubulin are A kinase anchor proteins for type I P...	KEEP AS NON CORE	Summary: PMID:19056362 showed the tubulin-PKA complex is transported to synapses, and PKA RI co-localized with tubulin in neuropils. Reason: Microtubules extend into synaptic regions and tubulin-PKA complexes are transported to synapses. This is a valid but non-core localization for Tuba1a. Supporting Evidence: PMID:19056362 it is mainly produced in the cytosol, and then transported to the synapses
GO:0046982 protein heterodimerization activity	IMP PMID:17218254 Mutations in alpha-tubulin cause abnormal neuronal migration...	ACCEPT	Summary: PMID:17218254 directly demonstrated that the S140G mutation reduces heterodimer formation using in vitro folding assays with 35S-labeled Tuba1a. Reason: Core molecular function. Heterodimer formation with beta-tubulin is the primary functional activity of alpha-tubulin. Directly demonstrated by biochemical assays. Supporting Evidence: PMID:17218254 Consistent with the data obtained in our GTP labeling experiments, we found that the S140G mutation reduced the efficiency of de novo heterodimer formation
GO:1902065 response to L-glutamate	IDA PMID:20037577 HDAC1 nuclear export induced by pathological conditions is e...	MARK AS OVER ANNOTATED	Summary: PMID:20037577 showed that glutamate exposure of neurons induces HDAC1 nuclear export and impaired mitochondrial transport in axons. Tubulin is part of the affected cytoskeleton. Reason: Same as the TNF response annotation. Tuba1a is not actively responding to glutamate; it is part of the cytoskeleton that is damaged by excitotoxic conditions. The response is mediated by HDAC1, not by tubulin. Supporting Evidence: PMID:20037577 cultured neurons exposed to glutamate and tumor necrosis factor-alpha
GO:0043209 myelin sheath	HDA PMID:17634366 Proteolipid protein is required for transport of sirtuin 2 i...	KEEP AS NON CORE	Summary: PMID:17634366 identified alpha-tubulin in purified myelin membranes by proteomics. The study identified >160 proteins in purified myelin membranes. Reason: Tubulin was detected in myelin proteomics as it is an extremely abundant cytoplasmic protein present in oligodendrocyte processes. This is not a primary localization for Tuba1a. Supporting Evidence: PMID:17634366 By gel-based proteome analysis, we identified >160 proteins in purified myelin membranes
GO:0005881 cytoplasmic microtubule	IDA PMID:19103752 Inhibition of microtubule assembly in osteoblasts stimulates...	ACCEPT	Summary: PMID:19103752 showed that inhibition of microtubule assembly in osteoblasts stimulates BMP-2 expression through Gli2. Alpha-tubulin is a component of cytoplasmic microtubules that were disrupted in this study. Reason: Correct localization. Tuba1a is a component of cytoplasmic microtubules. Consistent with the core function of alpha-tubulin.
GO:0005881 cytoplasmic microtubule	IDA PMID:17686994 The synovial sarcoma SYT-SSX2 oncogene remodels the cytoskel...	ACCEPT	Summary: PMID:17686994 studied SYT-SSX2 oncogene remodeling of the cytoskeleton. The study detected alpha-tubulin in cytoplasmic microtubules as part of the investigation. Reason: Correct localization. Alpha-tubulin is a fundamental component of cytoplasmic microtubules.

Core Functions

Tuba1a is a structural alpha-tubulin subunit of the microtubule cytoskeleton. Alpha/beta-tubulin heterodimers polymerize into cytoplasmic microtubules that organize cell architecture and provide tracks for microtubule-dependent processes.

Molecular Function:

structural constituent of cytoskeleton

Directly Involved In:

microtubule cytoskeleton organization microtubule polymerization

Cellular Locations:

microtubule microtubule cytoskeleton cytoplasmic microtubule

Supporting Evidence:

file:mouse/Tuba1a/Tuba1a-uniprot.txt
Tubulin is the major constituent of microtubules, protein filaments consisting of alpha- and beta-tubulin heterodimers.
PMID:17218254
The S140G Mutation Reduces GTP Binding and Native Heterodimer Formation
PMID:32184299
reduced TUBA1A allows for assembly of less microtubules in axons
file:mouse/Tuba1a/Tuba1a-deep-research-falcon.md
TUBA1A is a structural microtubule subunit that contributes alpha-tubulin to the alpha/beta heterodimer and thereby to the polymerized microtubule lattice.

Tuba1a binds GTP at the alpha-tubulin N-site, which stabilizes the alpha/beta-tubulin heterodimer needed for microtubule polymerization.

Molecular Function:

GTP binding

Directly Involved In:

microtubule polymerization

Supporting Evidence:

PMID:17218254
The S140G Mutation Reduces GTP Binding and Native Heterodimer FormationWe hypothesized that the S140G mutation might affect the ability of Tuba1 to bind GTP at the N site
file:mouse/Tuba1a/Tuba1a-uniprot.txt
Microtubules grow by the addition of GTP-tubulin dimers to the microtubule end, where a stabilizing cap forms.

Tuba1a heterodimerizes with beta-tubulin after chaperone-dependent folding, generating the alpha/beta-tubulin heterodimer that is the immediate building block of microtubules.

Molecular Function:

protein heterodimerization activity

Directly Involved In:

microtubule polymerization

Cellular Locations:

cytosol microtubule

Supporting Evidence:

PMID:17218254
Consistent with the data obtained in our GTP labeling experiments, we found that the S140G mutation reduced the efficiency of de novo heterodimer formation.
PMID:20603323
Disease-associated mutations in TUBA1A result in a spectrum of defects in the tubulin folding and heterodimer assembly pathway
file:mouse/Tuba1a/Tuba1a-deep-research-falcon.md
Microtubules are cytoskeletal polymers built from alpha/beta-tubulin heterodimers; TUBA1A is the predominant neuronal alpha-tubulin during brain development.

Tuba1a-rich neuronal microtubules support neuronal migration in the developing brain. Independent mouse alleles show that altered Tuba1a disrupts microtubule geometry, nucleus-centrosome coupling, and radial or saltatory neuronal migration.

Molecular Function:

structural constituent of cytoskeleton

Directly Involved In:

neuron migration

Cellular Locations:

cytoplasmic microtubule

Supporting Evidence:

PMID:17218254
The mutation results in abnormal neuronal migration in vivo; perturbations in layers II/III and IV of the visual, auditory, and somatosensory cortices; and a fractured pyramidal cell layer in the hippocampus
PMID:28687665
Live imaging of Tuba1a-mutant neurons revealed slowed migration and increased neuronal branching, which correlated with directionality alterations and perturbed nucleus-centrosome (N-C) coupling
PMID:31386652
In contrast, loss of Tuba1a is perinatal lethal and leads to significant forebrain dysmorphology
file:mouse/Tuba1a/Tuba1a-deep-research-falcon.md
A mouse Tuba1a S140G missense mutation results in straighter newly polymerized microtubules, slowed neuronal migration, increased branching, altered directionality, and perturbed nucleus-centrosome coupling in the rostral migratory stream.

Tuba1a is a structural component of mammalian sperm flagellar doublet microtubules. This is a precise cellular structural role; the broader sperm-motility phenotype is kept non-core because the direct evidence places Tuba1a in the axonemal microtubule lattice.

Molecular Function:

structural constituent of cytoskeleton

Cellular Locations:

sperm flagellum axonemal microtubule

Supporting Evidence:

PMID:37865089
Our in situ cryoET and subtomogram averaging has achieved up to 6.0 A reconstructions of native microtubule structures in mouse and human sperm samples.
file:mouse/Tuba1a/Tuba1a-uniprot.txt
Component of sperm flagellar doublet microtubules.

References

file:mouse/Tuba1a/Tuba1a-uniprot.txt

UniProt record for mouse Tuba1a (P68369)

Tuba1a is tubulin alpha-1A, a major constituent of microtubules that forms alpha/beta-tubulin heterodimers and is present in sperm flagellar doublet microtubules.
UniProt records GTP-tubulin dimers, Mg2+ cofactor use, and extensive alpha-tubulin post-translational modifications including acetylation, polyglutamylation, polyglycylation, and tyrosination/detyrosination.

file:mouse/Tuba1a/Tuba1a-deep-research-falcon.md

Falcon deep research report for mouse Tuba1a

Falcon verifies the target as mouse Tuba1a/P68369 and summarizes TUBA1A as a neuronal alpha-tubulin isotype that heterodimerizes with beta-tubulin and incorporates into microtubules.
Falcon supports TUBA1A as the predominant developmental neuronal alpha-tubulin, with Tuba1a-rich microtubules required for neurite extension, neuronal migration, axonal transport, and commissure formation.
Falcon summarizes mouse Tuba1a mutant evidence, including Tuba1aND dosage-sensitive commissural defects and S140G effects on microtubule straightness and neuronal saltatory migration.

GO_REF:0000002

InterPro2GO electronic annotation

GO_REF:0000033

Phylogenetic-based annotations by GO_Central (IBA)

GO_REF:0000044

UniProtKB-SubCell-based electronic annotation

GO_REF:0000096

ISO annotation from human ortholog via UniProt

GO_REF:0000107

ISO annotation from human ortholog

GO_REF:0000119

ISO annotation from human ortholog via GO_Central

GO_REF:0000120

UniProt Annotation Extension electronic annotation

PMID:17218254

Mutations in alpha-tubulin cause abnormal neuronal migration in mice and lissencephaly in humans.

S140G mutation in Tuba1a GTP binding pocket reduces GTP binding 5-fold and heterodimer formation
Impaired radial migration at E14.5 and E16.5 demonstrated by BrdU labeling
Fractured pyramidal cell layer in hippocampus and cortical wave-like perturbations
Hyperactivity, impaired spatial working memory, and reduced anxiety
BAC transgene rescue confirms all phenotypes are due to Tuba1a mutation
No cerebellar abnormalities

PMID:17634366

Proteolipid protein is required for transport of sirtuin 2 into CNS myelin.

Identified alpha-tubulin among >160 proteins in purified myelin membrane proteome

PMID:17686994

The synovial sarcoma SYT-SSX2 oncogene remodels the cytoskeleton through activation of the ephrin pathway.

SYT-SSX2 induces microtubule stabilization and accumulation of detyrosinated Glu-tubulin

PMID:19056362

Alpha/beta-tubulin are A kinase anchor proteins for type I PKA in neurons.

Alpha/beta-tubulin forms complex with PKA RI subunit serving as AKAP
Complex is produced in cytosol and transported to synapses
PKA RI co-localizes with tubulin in neuropils and at cell membrane

PMID:19103752

Inhibition of microtubule assembly in osteoblasts stimulates bone morphogenetic protein 2 expression and bone formation through transcription factor Gli2.

Microtubule inhibition increases Gli2 levels and BMP-2 expression in osteoblasts

PMID:19893491

CYLD negatively regulates cell-cycle progression by inactivating HDAC6 and increasing the levels of acetylated tubulin.

CYLD interacts with alpha-tubulin via CAP-Gly domains 1 and 2
CYLD inhibits HDAC6-mediated tubulin deacetylation
CYLD increases acetylated alpha-tubulin levels

PMID:20037577

HDAC1 nuclear export induced by pathological conditions is essential for the onset of axonal damage.

HDAC1 nuclear export in neurons exposed to glutamate and TNF-alpha
HDAC1 interacts with kinesin motor proteins impairing mitochondrial transport
Axonal damage involves cytoskeletal disruption including tubulin

PMID:20603323

Disease-associated mutations in TUBA1A result in a spectrum of defects in the tubulin folding and heterodimer assembly pathway.

Nine disease-causing TUBA1A mutations examined
Defects in chaperone interactions (prefoldin, CCT, TBCB)
Reduced heterodimer formation in varying yields
Suppressed microtubule growth rate in neurites

PMID:21041996

The role of Tuba1a in adult hippocampal neurogenesis and the formation of the dentate gyrus.

Normal neurogenic potential but ectopic neurogenesis in S140G mutant
Disorganized subgranular zone and dispersed granule cell layer
Defective migration of neurons and progenitors during development

PMID:21875651

Cytoarchitectural disruption of the superior colliculus and an enlarged acoustic startle response in the Tuba1a mutant mouse.

Superior colliculus thinning with apparent fusion of deep layers
Impaired radial migration in SC demonstrated by birthdate labeling
Massive neuronal loss attributed to increased apoptotic cell death
Exaggerated acoustic startle response

PMID:22101068

Behavioral and neuromorphological characterization of a novel Tuba1 mutant mouse.

D263G mutation (Rgsc1736 allele) causes hyperactivity and cortical abnormalities
Inattention to novel objects and aberrant home-cage activity patterns

PMID:24244602

TFIIB co-localizes and interacts with α-tubulin during oocyte meiosis in the mouse and depletion of TFIIB causes arrest of subsequent embryo development.

TFIIB and alpha-tubulin co-localize during meiosis
Direct interaction confirmed by BiFC
TFIIB associates with spindle microtubules from GVBD to MII

PMID:26658218

Novel α-tubulin mutation disrupts neural development and tubulin proteostasis.

Tuba1a ND mutation causes cortical dysgenesis and motor neuron defects
Motor neurons fail to innervate limb muscles with synapse defects at NMJ
Mutant alpha-tubulin depleted from cell lysate and microtubules
Tubulin-binding cofactors suppress mutation effects

PMID:27793670

Ciliary smoothened-mediated noncanonical hedgehog signaling promotes tubulin acetylation.

Hh pathway increases microtubule acetylation via Smo
Dependent on Smo but not Sufu or Gli
Requires primary cilia and intracellular calcium increase

PMID:27976998

Acetylated tubulin is essential for touch sensation in mice.

Atat1 knockout mice lose mechanosensitivity
All cutaneous afferent subtypes have reduced mechanosensitivity
Acetylation maintains cellular elasticity required for mechanotransduction

PMID:28687665

Mutation of the α-tubulin Tuba1a leads to straighter microtubules and perturbs neuronal migration.

S140G mutation causes increased microtubule straightness
Slowed neuronal migration with increased branching
Perturbed nucleus-centrosome coupling
Glial cells dispersed along RMS
Tuba1a plays essential non-compensated role in saltatory migration

PMID:31386652

Differential requirements of tubulin genes in mammalian forebrain development.

Tuba1a null is perinatal lethal with significant forebrain dysmorphology
Tubb2a and Tubb2b nulls survive with mild phenotypes
Demonstrates non-redundant role of Tuba1a

PMID:32184299

Reduced TUBA1A Tubulin Causes Defects in Trafficking and Impaired Adult Motor Behavior.

Tuba1a ND heterozygotes have reduced microtubule tracks in axons
Increased organelle trafficking pausing
Adult-onset ataxia
Age-related NMJ synapse size reduction without neuronal death

PMID:37865089

De novo protein identification in mammalian sperm using in situ cryoelectron tomography and AlphaFold2 docking.

Tuba1a identified in sperm flagellar doublet microtubules by cryo-ET at 7.7 angstrom
Structure resolved as component of axonemal doublet microtubules

Deep Research

Falcon

(Tuba1a-deep-research-falcon.md)

this with annotations you find in gene/protein databases, but these can be outdated or inaccurate. Falcon Edison Scientific Literature 39 citations 2026-05-04T02:56:49.118433

The research report should be a detailed narrative explaining the function, biological processes, and localization of the gene product. Citations should be given for all claims.

You should prioritize authoritative reviews and primary scientific literature when conducting research. You can supplement
this with annotations you find in gene/protein databases, but these can be outdated or inaccurate.

We are specifically interested in the primary function of the gene - for enzymes, what reaction is catalyzed, and what is the substrate specificity? For transporters, what is the substrate? For structural proteins or adapters, what is the broader structural role? For signaling molecules, what is the role in the pathway.

We are interested in where in or outside the cell the gene product carries out its function.

We are also interested in the signaling or biochemical pathways in which the gene functions. We are less interested in broad pleiotropic effects, except where these elucidate the precise role.

Include evidence where possible. We are interested in both experimental evidence as well as inference from structure, evolution, or bioinformatic analysis. Precise studies should be prioritized over high-throughput, where available.

Research report: Mouse Tuba1a (TUBA1A; UniProt P68369) — functional annotation, pathways, localization, and recent advances

0) Target verification (mandatory identity check)

The requested target is mouse Tuba1a, encoding tubulin alpha‑1A chain (TUBA1A). The literature gathered here explicitly discusses Tuba1a/TUBA1A as a neuronal α‑tubulin isotype that heterodimerizes with β‑tubulin and polymerizes into microtubules, matching the UniProt description of a tubulin family protein with canonical α‑tubulin features and C‑terminal PTMs (buscaglia2020reducedtuba1atubulin pages 1-2, belvindrah2017mutationofthe pages 1-2, aiken2020tubulinmutationsin pages 1-2).

1) Key concepts and definitions (current understanding)

1.1 Microtubules, α/β‑tubulin heterodimers, and isotype biology

Microtubules are cytoskeletal polymers built from α/β‑tubulin heterodimers; tubulin isotypes (encoded by distinct genes) are highly similar and can copolymerize, but may confer specialized properties in certain contexts (aiken2020tubulinmutationsin pages 1-2, belvindrah2017mutationofthe pages 1-2). In developing neurons, microtubules are central to neurite extension, migration, and synapse formation (aiken2020tubulinmutationsin pages 1-2, buscaglia2020reducedtuba1atubulin pages 1-2).

1.2 What is special about TUBA1A/Tuba1a?

Multiple lines of evidence support that TUBA1A is the predominant neuronal α‑tubulin during brain development, with RNA-seq–based estimates that it comprises ~95% of α‑tubulin mRNA in developing neurons (aiken2020tubulinmutationsin pages 1-2, buscaglia2020reducedtuba1atubulin pages 1-2, buscaglia2021tuba1amicrotubulesestablish pages 27-31). Developmental expression is neuron-enriched (induced around terminal neuronal mitosis), detectable by ~E9.5 and persisting through early postnatal periods with later decline (buscaglia2021tuba1amicrotubulesestablish pages 27-31).

1.3 “Tubulin code” and PTMs relevant to TUBA1A-containing microtubules

Neuronal microtubules acquire post‑translational modifications (PTMs) and microtubule‑associated proteins (MAPs) that influence stability and interactions with motors and MAPs (buscaglia2020reducedtuba1atubulin pages 1-2, buscaglia2021tuba1amicrotubulesestablish pages 23-27). For TUBA1A specifically, evidence summarized in a mouse-focused dissertation chapter highlights that α‑tubulin can be tyrosinated/detyrosinated and polyglutamylated, with polyglutamylation reported as specific to TUBA1A/TUBA1B in that context and linked to severing/MAP/motor interactions (buscaglia2021tuba1amicrotubulesestablish pages 126-130). While not isotype-specific, K40 in α‑tubulin is a central PTM “hub” in the tubulin code (e.g., acetylation; and, newly, lactylation), with functional consequences for neuronal morphology (sun2024metabolicregulationof pages 1-2).

2) Canonical functional annotation (mouse evidence prioritized)

2.1 Primary molecular function

TUBA1A is a structural microtubule subunit: it contributes α‑tubulin to the α/β heterodimer and thereby to the polymerized microtubule lattice. In neurons, these microtubules serve two dominant functional roles:
1) Mechanical/architectural support for neurite extension and growth cone structure, and
2) Tracks for intracellular transport supporting organelle/cargo trafficking (buscaglia2020reducedtuba1atubulin pages 1-2).

2.2 Subcellular localization

TUBA1A localizes wherever neuronal microtubules are present, including axons and distal neuronal compartments such as growth cones. A practical demonstration is that His6-tagged wild-type TUBA1A can polymerize into microtubules visible in extracted neurons, including distal structures such as growth cones (buscaglia2021tuba1amicrotubulesestablish pages 134-138, buscaglia2022bridgingthegap pages 11-13).

2.3 Biological processes and pathways (process-level “pathways”)

Rather than belonging to a single linear signaling pathway, TUBA1A sits in a microtubule-dependent process network, including:
- Neurite outgrowth/axon extension (microtubule assembly and growth cone organization) (buscaglia2020reducedtuba1atubulin pages 1-2, buscaglia2022bridgingthegap pages 11-13)
- Neuronal migration, including saltatory migration and nucleus–centrosome coupling (belvindrah2017mutationofthe pages 1-2)
- Axonal transport/trafficking (organelle movement; pausing defects when TUBA1A is reduced) (buscaglia2020reducedtuba1atubulin pages 1-2)
- Midline commissure formation (corpus callosum and other commissures) (buscaglia2022bridgingthegap pages 8-9, buscaglia2021tuba1amicrotubulesestablish pages 59-64)

3) Isoform-specific neurodevelopmental roles: key mouse genetic evidence

Mouse genetics provides the strongest isoform-specific evidence because antibodies often cannot distinguish α‑tubulin isotypes (buscaglia2020reducedtuba1atubulin pages 1-2, buscaglia2021tuba1amicrotubulesestablish pages 59-64).

3.1 Tuba1a loss-of-function model (Tuba1aND, N102D)

A loss-of-function Tuba1aND allele reduces TUBA1A abundance and prevents its incorporation into polymerized microtubules (buscaglia2022bridgingthegap pages 8-9, buscaglia2022bridgingthegap pages 1-2).

Commissure formation is highly sensitive to Tuba1a dosage: In heterozygous Tuba1aND/+ brains, 93% (14/15) show severe commissural defects and 87% (13/15) show complete corpus callosum agenesis (buscaglia2022bridgingthegap pages 8-9). Electron microscopy quantification shows reduced corpus callosum axon density (p=0.03), while g-ratio and axon diameter are not significantly changed (buscaglia2021tuba1amicrotubulesestablish pages 59-64).

Growth cone/cytoskeletal mechanism: In cultured neurons from Tuba1aND/+ mice, the longest neurite length is reduced at DIV3 (p=0.02), growth cones show significantly altered F‑actin intensity (p=0.0014) and a changed acetylated‑tubulin:F‑actin ratio (p=0.0003), and the MAP Map1b fails to localize properly to growth cones (p=0.009) despite unchanged Map1b in whole brain lysate (p=0.98) (buscaglia2022bridgingthegap pages 11-13). These data support a model in which developmental Tuba1a-rich microtubules are required to establish the cytoskeletal organization needed for long-range axon extension and pathfinding (buscaglia2022bridgingthegap pages 11-13).

Trafficking and adult function: Reduced TUBA1A in developing axons yields “more pausing” during organelle trafficking in P0 neurons and is associated with adult-onset ataxia in heterozygotes (buscaglia2020reducedtuba1atubulin pages 1-2).

3.2 Tuba1a missense model (S140G)

A mouse Tuba1a S140G missense mutation (reported as linked to human cortical malformations) results in straighter newly polymerized microtubules, slowed neuronal migration, increased branching, altered directionality, and perturbed nucleus–centrosome coupling in the rostral migratory stream (belvindrah2017mutationofthe pages 1-2). This supports the concept that Tuba1a contributes to microtubule mechanical/biophysical properties needed for saltatory migration.

3.3 Mechanism-level expert analysis: why haploinsufficiency may be insufficient to explain many tubulinopathies

Aiken et al. argue that many disease-causing TUBA1A missense variants likely act via a dominant “poisoning” mechanism (mutant tubulin incorporates into microtubules and alters function), rather than solely by reduced tubulin supply; they note tubulin family redundancy can partially buffer deletions, but missense incorporation can still dominantly disrupt microtubule behavior (aiken2020tubulinmutationsin pages 1-2). This perspective is consistent with experimental observations that some mutant α‑tubulins can incorporate into microtubules in model systems (aiken2020tubulinmutationsin pages 1-2).

4) Recent developments and latest research (prioritizing 2023–2024)

4.1 2023: Synonymous/codon usage can be pathogenic for Tuba1a (mRNA-level mechanism)

A key 2023 insight is that altering the Tuba1a coding sequence without changing the protein sequence can still cause severe neurodevelopmental failure. Leca et al. engineered an exon-4 codon-modified allele (78.8% sequence homology to WT) with unchanged TUBA1A protein sequence; homozygotes are perinatally lethal and E16.5 embryos show ventricular enlargement and cortical thinning/disorganization with quantified reductions in neuronal layer and progenitor zone thickness (Ctip2+ layer thickness p<0.05; Pax6+ VZ thickness p<0.01 vs WT; n=5) (leca2023codonmodificationof pages 2-5). This provides direct evidence that functional annotation must consider tubulin mRNA regulation/stability (leca2023codonmodificationof pages 1-2).

4.2 2024: A cerebellar lncRNA (TubAR) promotes TUBB4A–TUBA1A heterodimers to maintain myelination

Liang et al. identified TubAR (AK035765; 7.3 kb), a cytoplasmic cerebellum-enriched lncRNA that physically complexes with multiple tubulins including TUBA1A and TUBB4A, promotes their interaction/heterodimer formation, and supports microtubule assembly (liang2024lncrnatubarcomplexes pages 1-2, liang2024lncrnatubarcomplexes pages 2-4). Cerebellum-specific knockdown reached ~50% efficiency and all 4/4 tested mice showed demyelination by MRI; larger behavioral cohorts showed reduced locomotor activity assessed by rotarod and open-field testing (e.g., expanded rotarod cohorts: shCtrl n=36, shTubAR-1 n=39, shTubAR-2 n=13) (liang2024lncrnatubarcomplexes pages 10-11, liang2024lncrnatubarcomplexes pages 12-13). Mechanistically, TUBB4A variants that disrupt TubAR/TUBA1A interactions fail to rescue TubAR-loss phenotypes in cellular assays, while engineered R2A/G variants that retain TUBA1A binding can rescue cell death (liang2024lncrnatubarcomplexes pages 10-11, liang2024lncrnatubarcomplexes pages 7-8).

4.3 2024: Transcriptional regulation—SALL2 directly activates Tuba1a to drive neural differentiation

Xiong et al. report that SALL2 is enriched in the developing mouse nervous system and is required for ESC-to-neural differentiation in vitro. They identify Tuba1a as a direct SALL2 target (promoter binding by ChIP-seq and ChIP-qPCR), show Sall2 KO reduces Tuba1a expression, and demonstrate DOX-inducible Tuba1a expression rescues multiple neural differentiation phenotypes (SOX1:GFP+ cells, neural marker expression, NSC derivation, and neural tube organoid formation) (xiong2024sall2regulatesneural pages 9-10, xiong2024sall2regulatesneural pages 10-11). This positions Tuba1a within a gene-regulatory program for neurogenesis rather than only as a structural endpoint.

4.4 2024: New “tubulin code” chemistry connects metabolism to neuronal microtubule dynamics

Sun et al. discovered α‑tubulin K40 lactylation (in soluble dimers), catalyzed primarily by HDAC6 (as a lactyltransferase) and regulated by intracellular lactate. Lactylated α‑tubulin increases neuronal microtubule dynamics and promotes neurite outgrowth and branching in cultured hippocampal neurons (sun2024metabolicregulationof pages 1-2). Although not isotype-specific, this is directly relevant to TUBA1A-containing neuronal microtubules because TUBA1A is the dominant developmental α‑tubulin and carries the same K40 site.

5) Current applications and real‑world implementations

5.1 Mouse models as functional “assays” for Tuba1a biology

Tuba1aND/+ serves as a relatively specific in vivo model for commissure formation and long-range axon pathfinding, showing severe corpus callosum defects while preserving cortical layering, allowing separation of axon guidance from gross lamination defects (buscaglia2022bridgingthegap pages 8-9, buscaglia2022bridgingthegap pages 1-2).
The same allele is used to model axonal transport defects and adult-onset ataxia, linking developmental microtubule composition to later neuronal maintenance (buscaglia2020reducedtuba1atubulin pages 1-2).

5.2 Experimental tool development (addressing tubulin isotype indistinguishability)

Because isotype-specific antibodies are limited, genetic and tagging approaches have been implemented:
- An internally inserted His6-tagged TUBA1A that still polymerizes into neuronal microtubules enables extraction-compatible imaging and biochemical assays in cells and neurons (buscaglia2021tuba1amicrotubulesestablish pages 78-82, buscaglia2022bridgingthegap pages 11-13).

5.3 Clinical genetics and diagnostics (2024 evidence)

Two 2024 studies illustrate real-world clinical use of TUBA1A knowledge:
- In a cohort of 102 children with brain malformations, singleton exome sequencing (ES) diagnosed 36% (37/102), increasing to 43% with research follow-up; TUBA1A accounted for 8/37 solved cases (~22% of solved singleton ES diagnoses) (kooshavar2024diagnosticutilityof pages 4-5).
- In a single-center pediatric tubulinopathy cohort (n=15), TUBA1A variants were 33.3% (5/15). In the TUBA1A subgroup, reported frequencies included dysgyria (pachygyria/polymicrogyria) 80% (4/5), seizures 60% (3/5), microcephaly 100% (5/5), cerebellar dysplasia 60% (3/5), and corpus callosum hypoplasia 80% (4/5) (son2024clinicalandgenetic pages 1-2, son2024clinicalandgenetic pages 2-4).

6) Relevant statistics and data highlights (from recent studies)

Key quantitative points supported by extracted evidence include:
- TUBA1A transcript dominance: ~95% of α‑tubulin mRNA in developing neurons (aiken2020tubulinmutationsin pages 1-2, buscaglia2021tuba1amicrotubulesestablish pages 27-31).
- Commissure phenotype penetrance in mouse: in Tuba1aND/+ brains, 87% complete corpus callosum agenesis and 93% severe commissural defects (buscaglia2022bridgingthegap pages 8-9).
- Cellular phenotypes in mouse neurons (examples): DIV3 longest neurite length reduced (p=0.02); growth cone F‑actin altered (p=0.0014); Map1b growth cone localization reduced (p=0.009) (buscaglia2022bridgingthegap pages 11-13).
- 2023 codon-modified allele: homozygous perinatal lethality; E16.5 reductions in Ctip2+ layer thickness (p<0.05) and Pax6+ VZ thickness (p<0.01) (leca2023codonmodificationof pages 2-5).
- 2024 clinical ES: diagnostic yield 36% singleton ES, rising to 43% with research follow-up; 8/37 solved cases due to TUBA1A (kooshavar2024diagnosticutilityof pages 4-5).

7) Figures (visual evidence)

Cropped figures from Buscaglia et al. (2022) show the commissural phenotypes and quantitative neurite/corpus callosum measurements used to functionally annotate Tuba1a.

Commissural defects and quantitative measurements: (buscaglia2022bridgingthegap media 3de6d65c)
Corpus callosum labeling/EM and quantitative axon density/myelination metrics: (buscaglia2022bridgingthegap media e9e2f4ef)
Neurite outgrowth quantitative panels: (buscaglia2022bridgingthegap media 7fb36dfa)

8) Evidence map (compact summary table)

Area	Key findings	Quantitative data	Source (authors/year/journal)	URL/DOI
Core identity	Mouse Tuba1a encodes TUBA1A / tubulin alpha-1A chain (UniProt P68369), a neuronal α-tubulin isotype that heterodimerizes with β-tubulin and incorporates into microtubule polymers; it is the predominant α-tubulin transcript in developing neurons and is required for neurite extension, migration, and intracellular transport.	~95% of α-tubulin mRNA in developing neurons; expression detectable from ~E9.5 and declines after early postnatal stages; Tuba1aND/+ developing brains show ~50% reduction in total α-tubulin protein (aiken2020tubulinmutationsin pages 1-2, buscaglia2021tuba1amicrotubulesestablish pages 27-31, buscaglia2020reducedtuba1atubulin pages 1-2)	Aiken et al. 2020, Cytoskeleton; Buscaglia et al. 2020, eNeuro	https://doi.org/10.1002/cm.21567 ; https://doi.org/10.1523/eneuro.0045-20.2020
Mouse model: Tuba1aND/+	Loss-of-function N102D allele reduces TUBA1A abundance and prevents incorporation into neuronal microtubules; heterozygotes retain cortical layering but show impaired axon extension, commissure formation, growth-cone defects, trafficking defects, and later adult motor impairment/ataxia. Homozygotes are neonatal lethal with severe brain malformations.	93% (14/15) severe commissural defects; 87% (13/15) complete corpus callosum agenesis; reduced corpus callosum axon density (p=0.03); longest neurite length reduced at DIV3 (p=0.02); growth-cone F-actin altered (p=0.0014); acetylated-tubulin:F-actin ratio changed (p=0.0003); Map1b growth-cone localization reduced (p=0.009); juvenile α-tubulin ~50% of WT (buscaglia2022bridgingthegap pages 8-9, buscaglia2022bridgingthegap pages 11-13, buscaglia2020reducedtuba1atubulin pages 1-2, buscaglia2021tuba1amicrotubulesestablish pages 59-64)	Buscaglia et al. 2022, Frontiers in Cell and Developmental Biology; Buscaglia et al. 2020, eNeuro	https://doi.org/10.3389/fcell.2021.789438 ; https://doi.org/10.1523/eneuro.0045-20.2020
Mouse model: Tuba1a S140G / Jna	Missense allele produces straighter newly polymerized microtubules, perturbs neuronal saltatory migration, alters nucleus–centrosome coupling, and increases neuronal branching/directionality defects; supports a non-compensated, isoform-specific role for Tuba1a in migration.	Quantitative values not provided in extracted text, but phenotype includes slowed migration and structural MT changes; heterozygous phenotype described as significant in mouse studies (belvindrah2017mutationofthe pages 1-2, bittermann2018therolesof pages 17-21)	Belvindrah et al. 2017, Journal of Cell Biology	https://doi.org/10.1083/jcb.201607074
Mouse model: codon-modified R402Hmod	Synonymous/codon-modified Tuba1a allele encodes unchanged TUBA1A protein sequence but alters mRNA sequence/stability, causing severe neurodevelopmental failure without changing amino-acid sequence.	Modified exon shows 78.8% homology to WT coding sequence; R402Hmod/R402Hmod mice are perinatally lethal; at E16.5, reduced Ctip2+ layer thickness (p<0.05) and reduced Pax6+ ventricular zone thickness (p<0.01 vs WT; p<0.05 vs heterozygote); analysis n=5 (leca2023codonmodificationof pages 2-5, leca2023codonmodificationof pages 1-2)	Leca et al. 2023, Scientific Reports	https://doi.org/10.1038/s41598-023-27782-2
2024 advance: TubAR lncRNA	Cerebellar lncRNA TubAR forms a complex with TUBA1A and TUBB4A, promotes α/β heterodimer formation and microtubule assembly, and is required for myelination maintenance; TubAR loss causes demyelination, oligodendrocyte/Purkinje-cell loss, and reduced locomotor activity.	TubAR is a 7.3-kb transcript; in vivo knockdown achieved ~50% reduction; all 4/4 MRI-evaluated knockdown mice showed demyelination; behavioral cohorts included rotarod (n=36 shCtrl, n=39 shTubAR-1, n=13 shTubAR-2) and open field (n=10/group) (liang2024lncrnatubarcomplexes pages 1-2, liang2024lncrnatubarcomplexes pages 2-4, liang2024lncrnatubarcomplexes pages 10-11, liang2024lncrnatubarcomplexes pages 12-13)	Liang et al. 2024, Cell Discovery	https://doi.org/10.1038/s41421-024-00667-y
2024 advance: SALL2 → Tuba1a regulation	SALL2 is highly expressed in developing mouse nervous system and directly regulates Tuba1a during ESC neural differentiation; ChIP-seq/ChIP-qPCR show promoter binding, and inducible Tuba1a expression rescues Sall2-KO neural differentiation, NSC derivation, and neural tube organoid defects.	ChIP-seq identified 131 genomic targets; SOX1:GFP+ cells in Sall2-KO neural tube organoids significantly reduced (P<0.0001); Tuba1a induction restored SOX1:GFP+, Nestin, Pax6, Tubb3, and enabled passagable SOX2+ NSCs (xiong2024sall2regulatesneural pages 6-9, xiong2024sall2regulatesneural pages 10-11, xiong2024sall2regulatesneural pages 9-10, xiong2024sall2regulatesneural pages 1-2)	Xiong et al. 2024, Cell Death & Disease	https://doi.org/10.1038/s41419-024-07088-5
2024 advance: α-tubulin K40 lactylation	A new α-tubulin PTM, K40 lactylation, was shown to increase microtubule dynamics and promote neurite outgrowth/branching in neurons; although not Tuba1a-isotype-specific, it is directly relevant to TUBA1A-containing neuronal microtubules and the tubulin code.	K40 lactylation occurs on soluble α/β dimers; HDAC6 acts as a primary lactyltransferase; extracted text reports enhanced neurite outgrowth/branching but no numeric effect size in provided pages (sun2024metabolicregulationof pages 1-2)	Sun et al. 2024, Nature Communications	https://doi.org/10.1038/s41467-024-52729-0
2024 clinical/diagnostic cohort: brain malformations	In a 2024 exome-sequencing study of pediatric brain malformations, TUBA1A was the most frequent single-gene diagnosis, supporting routine inclusion in diagnostic pipelines for tubulinopathy/lissencephaly-spectrum disorders.	Cohort 102 children; singleton ES diagnostic yield 36% (37/102), rising to 43% after research follow-up; TUBA1A accounted for 8/37 solved singleton-ES diagnoses (~22% of solved cases); malformation subtypes included tubulinopathy 10% and lissencephaly 10% (kooshavar2024diagnosticutilityof pages 4-5, kooshavar2024diagnosticutilityof pages 1-3)	Kooshavar et al. 2024, Brain Communications	https://doi.org/10.1093/braincomms/fcae056
2024 clinical/diagnostic cohort: tubulinopathy spectrum	Single-center pediatric tubulinopathy cohort showed TUBA1A is a major contributor and is strongly associated with cortical dysgyria, microcephaly, seizures, cerebellar dysplasia, and corpus callosum hypoplasia.	Cohort 15 patients; TUBA1A n=5 (33.3%); overall microcephaly 10/15 (66.7%), seizures 9/15 (60%); within TUBA1A subgroup: pachygyria/polymicrogyria 4/5 (80%), cerebellar hypoplasia/dysplasia 3/5 (60%), seizures 3/5 (60%), microcephaly 5/5 (100%), corpus callosum hypoplasia 4/5 (80%) (son2024clinicalandgenetic pages 1-2, son2024clinicalandgenetic pages 2-4)	Son et al. 2024, Annals of Child Neurology	https://doi.org/10.26815/acn.2024.00423

Table: This table concisely summarizes verified identity, major mouse genetic models, key 2023-2024 mechanistic advances, and recent clinical diagnostic statistics for mouse Tuba1a/TUBA1A. It is useful as a compact evidence map linking basic function, model phenotypes, and translational relevance.

9) Practical functional annotation summary (for databases)

Protein/gene: Tuba1a (mouse) → TUBA1A α‑tubulin; core subunit of microtubules (buscaglia2020reducedtuba1atubulin pages 1-2, belvindrah2017mutationofthe pages 1-2).
Primary function: structural α‑tubulin in α/β heterodimers; supports microtubule polymerization that underlies neurite extension, neuronal migration, and transport (buscaglia2020reducedtuba1atubulin pages 1-2, belvindrah2017mutationofthe pages 1-2).
Localization: microtubule cytoskeleton in neuronal compartments including growth cones (buscaglia2022bridgingthegap pages 11-13, buscaglia2021tuba1amicrotubulesestablish pages 78-82).
Key processes: commissure formation/axon pathfinding (high dosage sensitivity), axonal transport, neuronal migration, synapse maintenance (buscaglia2022bridgingthegap pages 8-9, buscaglia2020reducedtuba1atubulin pages 1-2, belvindrah2017mutationofthe pages 1-2).
Regulation: (i) transcriptional control by SALL2 during neural differentiation (xiong2024sall2regulatesneural pages 9-10); (ii) mRNA-level sensitivity to synonymous codon usage (leca2023codonmodificationof pages 2-5); (iii) functionally relevant PTMs on α‑tubulin, including newly described K40 lactylation affecting neurite outgrowth (sun2024metabolicregulationof pages 1-2).

References (URLs and publication dates available in evidence)

Key sources include: Buscaglia et al. Frontiers in Cell and Developmental Biology (Jan 2022) https://doi.org/10.3389/fcell.2021.789438 (buscaglia2022bridgingthegap pages 8-9); Buscaglia et al. eNeuro (Mar 2020) https://doi.org/10.1523/eneuro.0045-20.2020 (buscaglia2020reducedtuba1atubulin pages 1-2); Belvindrah et al. J Cell Biol (Aug 2017) https://doi.org/10.1083/jcb.201607074 (belvindrah2017mutationofthe pages 1-2); Leca et al. Scientific Reports (Jan 2023) https://doi.org/10.1038/s41598-023-27782-2 (leca2023codonmodificationof pages 2-5); Liang et al. Cell Discovery (May 2024) https://doi.org/10.1038/s41421-024-00667-y (liang2024lncrnatubarcomplexes pages 1-2); Xiong et al. Cell Death & Disease (Sep 2024) https://doi.org/10.1038/s41419-024-07088-5 (xiong2024sall2regulatesneural pages 9-10); Sun et al. Nature Communications (Sep 2024) https://doi.org/10.1038/s41467-024-52729-0 (sun2024metabolicregulationof pages 1-2); Kooshavar et al. Brain Communications (Feb 2024) https://doi.org/10.1093/braincomms/fcae056 (kooshavar2024diagnosticutilityof pages 4-5); Son et al. Annals of Child Neurology (Apr 2024) https://doi.org/10.26815/acn.2024.00423 (son2024clinicalandgenetic pages 1-2).

References

(buscaglia2020reducedtuba1atubulin pages 1-2): Georgia Buscaglia, Kyle R. Northington, Jeffrey K. Moore, and Emily Anne Bates. Reduced tuba1a tubulin causes defects in trafficking and impaired adult motor behavior. eNeuro, 7:ENEURO.0045-20.2020, Mar 2020. URL: https://doi.org/10.1523/eneuro.0045-20.2020, doi:10.1523/eneuro.0045-20.2020. This article has 33 citations and is from a peer-reviewed journal.
(belvindrah2017mutationofthe pages 1-2): Richard Belvindrah, Kathiresan Natarajan, Preety Shabajee, Elodie Bruel-Jungerman, Jennifer Bernard, Marie Goutierre, Imane Moutkine, Xavier H. Jaglin, Mythili Savariradjane, Theano Irinopoulou, Jean-Christophe Poncer, Carsten Janke, and Fiona Francis. Mutation of the α-tubulin tuba1a leads to straighter microtubules and perturbs neuronal migration. The Journal of Cell Biology, 216:2443-2461, Aug 2017. URL: https://doi.org/10.1083/jcb.201607074, doi:10.1083/jcb.201607074. This article has 79 citations.
(aiken2020tubulinmutationsin pages 1-2): Jayne Aiken, Georgia Buscaglia, A. Sophie Aiken, Jeffrey K. Moore, and Emily A. Bates. Tubulin mutations in brain development disorders: why haploinsufficiency does not explain tuba1a tubulinopathies. Cytoskeleton, 77:40-54, Mar 2020. URL: https://doi.org/10.1002/cm.21567, doi:10.1002/cm.21567. This article has 43 citations and is from a peer-reviewed journal.
(buscaglia2021tuba1amicrotubulesestablish pages 27-31): Georgia Christine Buscaglia. Tuba1a microtubules establish the foundations for neuronal function. Other, Jan 2021. URL: https://doi.org/10.25677/wrsv-fy33, doi:10.25677/wrsv-fy33. This article has 0 citations.
(buscaglia2021tuba1amicrotubulesestablish pages 23-27): Georgia Christine Buscaglia. Tuba1a microtubules establish the foundations for neuronal function. Other, Jan 2021. URL: https://doi.org/10.25677/wrsv-fy33, doi:10.25677/wrsv-fy33. This article has 0 citations.
(buscaglia2021tuba1amicrotubulesestablish pages 126-130): Georgia Christine Buscaglia. Tuba1a microtubules establish the foundations for neuronal function. Other, Jan 2021. URL: https://doi.org/10.25677/wrsv-fy33, doi:10.25677/wrsv-fy33. This article has 0 citations.
(sun2024metabolicregulationof pages 1-2): Shuangshuang Sun, Zhenli Xu, Liying He, Yihui Shen, Yuqing Yan, Xubing Lv, Xujing Zhu, Wei Li, Wei-Ya Tian, Yongjun Zheng, Sen Lin, Yadong Sun, and Lei Li. Metabolic regulation of cytoskeleton functions by hdac6-catalyzed α-tubulin lactylation. Nature Communications, Sep 2024. URL: https://doi.org/10.1038/s41467-024-52729-0, doi:10.1038/s41467-024-52729-0. This article has 91 citations and is from a highest quality peer-reviewed journal.
(buscaglia2021tuba1amicrotubulesestablish pages 134-138): Georgia Christine Buscaglia. Tuba1a microtubules establish the foundations for neuronal function. Other, Jan 2021. URL: https://doi.org/10.25677/wrsv-fy33, doi:10.25677/wrsv-fy33. This article has 0 citations.
(buscaglia2022bridgingthegap pages 11-13): Georgia Buscaglia, Kyle R. Northington, Jayne Aiken, Katelyn J. Hoff, and Emily A. Bates. Bridging the gap: the importance of tuba1a α-tubulin in forming midline commissures. Frontiers in Cell and Developmental Biology, Jan 2022. URL: https://doi.org/10.3389/fcell.2021.789438, doi:10.3389/fcell.2021.789438. This article has 19 citations.
(buscaglia2022bridgingthegap pages 8-9): Georgia Buscaglia, Kyle R. Northington, Jayne Aiken, Katelyn J. Hoff, and Emily A. Bates. Bridging the gap: the importance of tuba1a α-tubulin in forming midline commissures. Frontiers in Cell and Developmental Biology, Jan 2022. URL: https://doi.org/10.3389/fcell.2021.789438, doi:10.3389/fcell.2021.789438. This article has 19 citations.
(buscaglia2021tuba1amicrotubulesestablish pages 59-64): Georgia Christine Buscaglia. Tuba1a microtubules establish the foundations for neuronal function. Other, Jan 2021. URL: https://doi.org/10.25677/wrsv-fy33, doi:10.25677/wrsv-fy33. This article has 0 citations.
(buscaglia2022bridgingthegap pages 1-2): Georgia Buscaglia, Kyle R. Northington, Jayne Aiken, Katelyn J. Hoff, and Emily A. Bates. Bridging the gap: the importance of tuba1a α-tubulin in forming midline commissures. Frontiers in Cell and Developmental Biology, Jan 2022. URL: https://doi.org/10.3389/fcell.2021.789438, doi:10.3389/fcell.2021.789438. This article has 19 citations.
(leca2023codonmodificationof pages 2-5): Ines Leca, Alexander William Phillips, Lyubov Ushakova, Thomas David Cushion, and David Anthony Keays. Codon modification of tuba1a alters mrna levels and causes a severe neurodevelopmental phenotype in mice. Scientific Reports, Jan 2023. URL: https://doi.org/10.1038/s41598-023-27782-2, doi:10.1038/s41598-023-27782-2. This article has 9 citations and is from a peer-reviewed journal.
(leca2023codonmodificationof pages 1-2): Ines Leca, Alexander William Phillips, Lyubov Ushakova, Thomas David Cushion, and David Anthony Keays. Codon modification of tuba1a alters mrna levels and causes a severe neurodevelopmental phenotype in mice. Scientific Reports, Jan 2023. URL: https://doi.org/10.1038/s41598-023-27782-2, doi:10.1038/s41598-023-27782-2. This article has 9 citations and is from a peer-reviewed journal.
(liang2024lncrnatubarcomplexes pages 1-2): Xiaolin Liang, Meng Gong, Zhikai Wang, Jie Wang, Weiwei Guo, Aoling Cai, Zhenye Yang, Xing Liu, Fuqiang Xu, Wei Xiong, Chuanhai Fu, and Xiangting Wang. Lncrna tubar complexes with tubb4a and tuba1a to promote microtubule assembly and maintain myelination. Cell Discovery, May 2024. URL: https://doi.org/10.1038/s41421-024-00667-y, doi:10.1038/s41421-024-00667-y. This article has 9 citations and is from a peer-reviewed journal.
(liang2024lncrnatubarcomplexes pages 2-4): Xiaolin Liang, Meng Gong, Zhikai Wang, Jie Wang, Weiwei Guo, Aoling Cai, Zhenye Yang, Xing Liu, Fuqiang Xu, Wei Xiong, Chuanhai Fu, and Xiangting Wang. Lncrna tubar complexes with tubb4a and tuba1a to promote microtubule assembly and maintain myelination. Cell Discovery, May 2024. URL: https://doi.org/10.1038/s41421-024-00667-y, doi:10.1038/s41421-024-00667-y. This article has 9 citations and is from a peer-reviewed journal.
(liang2024lncrnatubarcomplexes pages 10-11): Xiaolin Liang, Meng Gong, Zhikai Wang, Jie Wang, Weiwei Guo, Aoling Cai, Zhenye Yang, Xing Liu, Fuqiang Xu, Wei Xiong, Chuanhai Fu, and Xiangting Wang. Lncrna tubar complexes with tubb4a and tuba1a to promote microtubule assembly and maintain myelination. Cell Discovery, May 2024. URL: https://doi.org/10.1038/s41421-024-00667-y, doi:10.1038/s41421-024-00667-y. This article has 9 citations and is from a peer-reviewed journal.
(liang2024lncrnatubarcomplexes pages 12-13): Xiaolin Liang, Meng Gong, Zhikai Wang, Jie Wang, Weiwei Guo, Aoling Cai, Zhenye Yang, Xing Liu, Fuqiang Xu, Wei Xiong, Chuanhai Fu, and Xiangting Wang. Lncrna tubar complexes with tubb4a and tuba1a to promote microtubule assembly and maintain myelination. Cell Discovery, May 2024. URL: https://doi.org/10.1038/s41421-024-00667-y, doi:10.1038/s41421-024-00667-y. This article has 9 citations and is from a peer-reviewed journal.
(liang2024lncrnatubarcomplexes pages 7-8): Xiaolin Liang, Meng Gong, Zhikai Wang, Jie Wang, Weiwei Guo, Aoling Cai, Zhenye Yang, Xing Liu, Fuqiang Xu, Wei Xiong, Chuanhai Fu, and Xiangting Wang. Lncrna tubar complexes with tubb4a and tuba1a to promote microtubule assembly and maintain myelination. Cell Discovery, May 2024. URL: https://doi.org/10.1038/s41421-024-00667-y, doi:10.1038/s41421-024-00667-y. This article has 9 citations and is from a peer-reviewed journal.
(xiong2024sall2regulatesneural pages 9-10): Hui Xiong, Bowen Lin, Junyang Liu, Renhong Lu, Zheyi Lin, Chengwen Hang, Wenjun Liu, Lei Zhang, Jie Ding, Huixin Guo, Mingshuai Zhang, Siyu Wang, Zheng Gong, Duanyang Xie, Yi Liu, Dan Shi, Dandan Liang, Zhen Liu, Yi-Han Chen, and Jian Yang. Sall2 regulates neural differentiation of mouse embryonic stem cells through tuba1a. Cell Death & Disease, Sep 2024. URL: https://doi.org/10.1038/s41419-024-07088-5, doi:10.1038/s41419-024-07088-5. This article has 5 citations and is from a peer-reviewed journal.
(xiong2024sall2regulatesneural pages 10-11): Hui Xiong, Bowen Lin, Junyang Liu, Renhong Lu, Zheyi Lin, Chengwen Hang, Wenjun Liu, Lei Zhang, Jie Ding, Huixin Guo, Mingshuai Zhang, Siyu Wang, Zheng Gong, Duanyang Xie, Yi Liu, Dan Shi, Dandan Liang, Zhen Liu, Yi-Han Chen, and Jian Yang. Sall2 regulates neural differentiation of mouse embryonic stem cells through tuba1a. Cell Death & Disease, Sep 2024. URL: https://doi.org/10.1038/s41419-024-07088-5, doi:10.1038/s41419-024-07088-5. This article has 5 citations and is from a peer-reviewed journal.
(buscaglia2021tuba1amicrotubulesestablish pages 78-82): Georgia Christine Buscaglia. Tuba1a microtubules establish the foundations for neuronal function. Other, Jan 2021. URL: https://doi.org/10.25677/wrsv-fy33, doi:10.25677/wrsv-fy33. This article has 0 citations.
(kooshavar2024diagnosticutilityof pages 4-5): Daniz Kooshavar, David J Amor, Kirsten Boggs, Naomi Baker, Christopher Barnett, Michelle G de Silva, Samantha Edwards, Michael C Fahey, Justine E Marum, Penny Snell, Kiymet Bozaoglu, Kate Pope, Shekeeb S Mohammad, Kate Riney, Rani Sachdev, Ingrid E Scheffer, Sarah Schenscher, John Silberstein, Nicholas Smith, Melanie Tom, Tyson L Ware, Paul J Lockhart, and Richard J Leventer. Diagnostic utility of exome sequencing followed by research reanalysis in human brain malformations. Brain Communications, Feb 2024. URL: https://doi.org/10.1093/braincomms/fcae056, doi:10.1093/braincomms/fcae056. This article has 6 citations and is from a peer-reviewed journal.
(son2024clinicalandgenetic pages 1-2): Hey-Joon Son, Minhye Kim, Hye Jin Kim, Jae So Cho, Soo Yeon Kim, Byung Chan Lim, Ki Joong Kim, Jong-Hee Chae, and Woo Joong Kim. Clinical and genetic spectrum of tubulinopathy: a single-center study. Annals of Child Neurology, 32:115-121, Apr 2024. URL: https://doi.org/10.26815/acn.2024.00423, doi:10.26815/acn.2024.00423. This article has 4 citations.
(son2024clinicalandgenetic pages 2-4): Hey-Joon Son, Minhye Kim, Hye Jin Kim, Jae So Cho, Soo Yeon Kim, Byung Chan Lim, Ki Joong Kim, Jong-Hee Chae, and Woo Joong Kim. Clinical and genetic spectrum of tubulinopathy: a single-center study. Annals of Child Neurology, 32:115-121, Apr 2024. URL: https://doi.org/10.26815/acn.2024.00423, doi:10.26815/acn.2024.00423. This article has 4 citations.
(buscaglia2022bridgingthegap media 3de6d65c): Georgia Buscaglia, Kyle R. Northington, Jayne Aiken, Katelyn J. Hoff, and Emily A. Bates. Bridging the gap: the importance of tuba1a α-tubulin in forming midline commissures. Frontiers in Cell and Developmental Biology, Jan 2022. URL: https://doi.org/10.3389/fcell.2021.789438, doi:10.3389/fcell.2021.789438. This article has 19 citations.
(buscaglia2022bridgingthegap media e9e2f4ef): Georgia Buscaglia, Kyle R. Northington, Jayne Aiken, Katelyn J. Hoff, and Emily A. Bates. Bridging the gap: the importance of tuba1a α-tubulin in forming midline commissures. Frontiers in Cell and Developmental Biology, Jan 2022. URL: https://doi.org/10.3389/fcell.2021.789438, doi:10.3389/fcell.2021.789438. This article has 19 citations.
(buscaglia2022bridgingthegap media 7fb36dfa): Georgia Buscaglia, Kyle R. Northington, Jayne Aiken, Katelyn J. Hoff, and Emily A. Bates. Bridging the gap: the importance of tuba1a α-tubulin in forming midline commissures. Frontiers in Cell and Developmental Biology, Jan 2022. URL: https://doi.org/10.3389/fcell.2021.789438, doi:10.3389/fcell.2021.789438. This article has 19 citations.
(bittermann2018therolesof pages 17-21): EA Bittermann. The roles of tubulins in the developing mouse brain. Unknown journal, 2018.
(xiong2024sall2regulatesneural pages 6-9): Hui Xiong, Bowen Lin, Junyang Liu, Renhong Lu, Zheyi Lin, Chengwen Hang, Wenjun Liu, Lei Zhang, Jie Ding, Huixin Guo, Mingshuai Zhang, Siyu Wang, Zheng Gong, Duanyang Xie, Yi Liu, Dan Shi, Dandan Liang, Zhen Liu, Yi-Han Chen, and Jian Yang. Sall2 regulates neural differentiation of mouse embryonic stem cells through tuba1a. Cell Death & Disease, Sep 2024. URL: https://doi.org/10.1038/s41419-024-07088-5, doi:10.1038/s41419-024-07088-5. This article has 5 citations and is from a peer-reviewed journal.
(xiong2024sall2regulatesneural pages 1-2): Hui Xiong, Bowen Lin, Junyang Liu, Renhong Lu, Zheyi Lin, Chengwen Hang, Wenjun Liu, Lei Zhang, Jie Ding, Huixin Guo, Mingshuai Zhang, Siyu Wang, Zheng Gong, Duanyang Xie, Yi Liu, Dan Shi, Dandan Liang, Zhen Liu, Yi-Han Chen, and Jian Yang. Sall2 regulates neural differentiation of mouse embryonic stem cells through tuba1a. Cell Death & Disease, Sep 2024. URL: https://doi.org/10.1038/s41419-024-07088-5, doi:10.1038/s41419-024-07088-5. This article has 5 citations and is from a peer-reviewed journal.
(kooshavar2024diagnosticutilityof pages 1-3): Daniz Kooshavar, David J Amor, Kirsten Boggs, Naomi Baker, Christopher Barnett, Michelle G de Silva, Samantha Edwards, Michael C Fahey, Justine E Marum, Penny Snell, Kiymet Bozaoglu, Kate Pope, Shekeeb S Mohammad, Kate Riney, Rani Sachdev, Ingrid E Scheffer, Sarah Schenscher, John Silberstein, Nicholas Smith, Melanie Tom, Tyson L Ware, Paul J Lockhart, and Richard J Leventer. Diagnostic utility of exome sequencing followed by research reanalysis in human brain malformations. Brain Communications, Feb 2024. URL: https://doi.org/10.1093/braincomms/fcae056, doi:10.1093/braincomms/fcae056. This article has 6 citations and is from a peer-reviewed journal.

Citations

sun2024metabolicregulationof pages 1-2
belvindrah2017mutationofthe pages 1-2
buscaglia2022bridgingthegap pages 8-9
buscaglia2022bridgingthegap pages 11-13
aiken2020tubulinmutationsin pages 1-2
leca2023codonmodificationof pages 2-5
leca2023codonmodificationof pages 1-2
kooshavar2024diagnosticutilityof pages 4-5
liang2024lncrnatubarcomplexes pages 1-2
son2024clinicalandgenetic pages 1-2
buscaglia2022bridgingthegap pages 1-2
liang2024lncrnatubarcomplexes pages 2-4
liang2024lncrnatubarcomplexes pages 10-11
liang2024lncrnatubarcomplexes pages 12-13
liang2024lncrnatubarcomplexes pages 7-8
son2024clinicalandgenetic pages 2-4
bittermann2018therolesof pages 17-21
kooshavar2024diagnosticutilityof pages 1-3
https://doi.org/10.1002/cm.21567
https://doi.org/10.1523/eneuro.0045-20.2020
https://doi.org/10.3389/fcell.2021.789438
https://doi.org/10.1083/jcb.201607074
https://doi.org/10.1038/s41598-023-27782-2
https://doi.org/10.1038/s41421-024-00667-y
https://doi.org/10.1038/s41419-024-07088-5
https://doi.org/10.1038/s41467-024-52729-0
https://doi.org/10.1093/braincomms/fcae056
https://doi.org/10.26815/acn.2024.00423
https://doi.org/10.1523/eneuro.0045-20.2020,
https://doi.org/10.1083/jcb.201607074,
https://doi.org/10.1002/cm.21567,
https://doi.org/10.25677/wrsv-fy33,
https://doi.org/10.1038/s41467-024-52729-0,
https://doi.org/10.3389/fcell.2021.789438,
https://doi.org/10.1038/s41598-023-27782-2,
https://doi.org/10.1038/s41421-024-00667-y,
https://doi.org/10.1038/s41419-024-07088-5,
https://doi.org/10.1093/braincomms/fcae056,
https://doi.org/10.26815/acn.2024.00423,

📄 View Raw YAML

id: P68369
gene_symbol: Tuba1a
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:10090
  label: Mus musculus
description: Tuba1a encodes tubulin alpha-1A, a major neuronal alpha-tubulin isotype
  that is especially abundant during mouse brain development. It heterodimerizes with
  beta-tubulin to form GTP-bound alpha/beta-tubulin dimers that polymerize into microtubules;
  GTP binding at the alpha-tubulin N-site stabilizes the heterodimer, while the tubulin
  polymer cycle drives microtubule dynamics. Tuba1a-rich microtubules are required
  for neuronal migration, neurite extension, axon pathfinding, and axonal transport.
  Direct structural evidence also places Tuba1a in sperm flagellar doublet microtubules.
  The protein undergoes extensive post-translational modifications including acetylation,
  detyrosination, glutamylation, and glycylation that tune microtubule stability and
  motor-protein interactions.
existing_annotations:
# ============================================================
# IBA annotations (phylogenetic-based, from GO_REF:0000033)
# ============================================================
- term:
    id: GO:0000226
    label: microtubule cytoskeleton organization
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: Alpha-tubulin is a core structural component of microtubules, and its
      role in microtubule cytoskeleton organization is well established across the
      tubulin family. Tuba1a S140G mutant mice show disrupted microtubule organization
      in the brain (PMID:17218254, PMID:28687665).
    action: ACCEPT
    reason: Core function of alpha-tubulin. Mutations in Tuba1a directly impair microtubule
      cytoskeleton organization as demonstrated in multiple ENU mutant mouse studies.
    supported_by:
    - reference_id: PMID:17218254
      supporting_text: "the causative mutation lies in the guanosine triphosphate\
        \ (GTP) binding pocket of alpha-1 tubulin (Tuba1) and affects tubulin heterodimer\
        \ formation"
    - reference_id: PMID:28687665
      supporting_text: "Tuba1a mutation led to increased straightness of newly polymerized\
        \ MTs"
    - reference_id: file:mouse/Tuba1a/Tuba1a-deep-research-falcon.md
      supporting_text: Mouse Tuba1a encodes a neuronal alpha-tubulin isotype that
        heterodimerizes with beta-tubulin and incorporates into microtubule polymers;
        it is required for neurite extension, neuronal migration, and intracellular
        transport.
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: Alpha-tubulin is a cytoplasmic protein that forms microtubules in the
      cytoplasm. This is a fundamental localization for all tubulins.
    action: ACCEPT
    reason: Core localization for alpha-tubulin. Well established across all tubulin
      family members.
- term:
    id: GO:0005874
    label: microtubule
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: Alpha-tubulin is a structural component of microtubules, forming alpha/beta
      heterodimers that polymerize into the microtubule lattice. This is a core localization
      for Tuba1a.
    action: ACCEPT
    reason: Core localization. Alpha-tubulin is literally a building block of microtubules.
      UniProt confirms this is a major constituent of microtubules.
    supported_by:
    - reference_id: PMID:17218254
      supporting_text: "a FLAG-tagged mutant Tuba1 incorporated into the normal interphase\
        \ microtubule network upon overexperession in cultured cells"
- term:
    id: GO:0000278
    label: mitotic cell cycle
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: Alpha-tubulin is required for mitotic spindle formation during cell division.
      This is a conserved function across the tubulin family.
    action: KEEP_AS_NON_CORE
    reason: While microtubules are essential for mitotic spindle function, Tuba1a
      is primarily expressed in post-mitotic neurons (PMID:26658218). Other alpha-tubulin
      isotypes (e.g. Tuba1b, Tuba1c) are more likely the primary contributors to the
      mitotic spindle in dividing cells. Valid IBA annotation but not a core function
      of Tuba1a specifically.
- term:
    id: GO:0005200
    label: structural constituent of cytoskeleton
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: Alpha-tubulin is a core structural constituent of the microtubule cytoskeleton.
      This is the primary molecular function of alpha-tubulin.
    action: ACCEPT
    reason: This is the defining molecular function of alpha-tubulin. UniProt annotates
      it with EC 3.6.5.- and describes it as "the major constituent of microtubules."
- term:
    id: GO:0030182
    label: neuron differentiation
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: Tuba1a plays a key role in neuron differentiation through its requirement
      for neuronal migration and morphogenesis. Multiple Tuba1a mutant mice show defects
      in neuronal development (PMID:17218254, PMID:28687665, PMID:26658218).
    action: KEEP_AS_NON_CORE
    reason: Tuba1a is the predominant alpha-tubulin in post-mitotic neurons and is
      essential for neuronal morphogenesis, but the direct supported process is neuronal
      migration and microtubule-dependent neurite extension rather than differentiation
      fate specification.
    supported_by:
    - reference_id: PMID:26658218
      supporting_text: "Tuba1a is highly expressed in the brain during late embryonic\
        \ development, and specifically enriched in post-mitotic neurons that extend\
        \ long processes"
- term:
    id: GO:0005525
    label: GTP binding
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: Alpha-tubulin binds GTP at the non-exchangeable N-site, which acts as
      a structural cofactor stabilizing the alpha/beta heterodimer. This is a fundamental
      property of all alpha-tubulins.
    action: ACCEPT
    reason: Core molecular function. GTP binding is essential for tubulin heterodimer
      stability and microtubule polymerization. The Jenna (S140G) mutation directly
      affects GTP binding at the N-site (PMID:17218254).
    supported_by:
    - reference_id: PMID:17218254
      supporting_text: "The mutation causes an amino acid change from serine to glycine\
        \ at residue 140 (S140G)"
# ============================================================
# IEA annotations (electronic annotation)
# ============================================================
- term:
    id: GO:0005200
    label: structural constituent of cytoskeleton
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  review:
    summary: IEA annotation consistent with IBA annotation for the same term. Structural
      constituent of cytoskeleton is the core molecular function of alpha-tubulin.
    action: ACCEPT
    reason: Redundant with IBA annotation but correctly assigned. Core function.
- term:
    id: GO:0005525
    label: GTP binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  review:
    summary: IEA annotation consistent with IBA annotation for the same term. GTP
      binding is essential for tubulin function.
    action: ACCEPT
    reason: Redundant with IBA annotation but correctly assigned. Core function.
- term:
    id: GO:0005856
    label: cytoskeleton
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  review:
    summary: Tubulin is a component of the cytoskeleton. This is a broader parent
      term of microtubule cytoskeleton.
    action: ACCEPT
    reason: Correct but less specific than microtubule cytoskeleton (GO:0015630).
      Acceptable as a broader IEA term.
- term:
    id: GO:0005874
    label: microtubule
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: IEA annotation consistent with IBA annotation. Alpha-tubulin is a component
      of microtubules.
    action: ACCEPT
    reason: Redundant with IBA annotation but correctly assigned. Core localization.
- term:
    id: GO:0007017
    label: microtubule-based process
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  review:
    summary: Alpha-tubulin is involved in microtubule-based processes. This is a broad
      parent term.
    action: ACCEPT
    reason: Correct but very broad. Acceptable as an IEA annotation since more specific
      terms are also present.
# ============================================================
# IPI annotation for CYLD interaction (PMID:19893491)
# ============================================================
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:19893491
  review:
    summary: PMID:19893491 demonstrates that CYLD interacts with alpha-tubulin through
      its CAP-Gly domains. The interaction was shown by co-immunoprecipitation in
      keratinocytes and melanocytes. However, "protein binding" is uninformative.
    action: MARK_AS_OVER_ANNOTATED
    reason: The CYLD-alpha-tubulin interaction is experimentally supported, but GO:0005515
      is an uninformative generic binding term and does not capture a core Tuba1a
      activity. The functional direction in the paper is CYLD binding polymerized
      tubulin and regulating HDAC6-mediated tubulin acetylation, not a specific binding
      activity that should define Tuba1a function.
    supported_by:
    - reference_id: PMID:19893491
      supporting_text: "Immunoprecipitation of endogenous CYLD in melanocytes revealed\
        \ an interaction with alpha-tubulin"
# ============================================================
# IEA annotations from GO_REF:0000107 (ISO-based)
# ============================================================
- term:
    id: GO:0005879
    label: axonemal microtubule
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: Tuba1a has been directly identified as a component of sperm flagellar
      doublet microtubules by cryo-ET (PMID:37865089). Axonemal microtubules are the
      doublet microtubules found in cilia and flagella.
    action: ACCEPT
    reason: Directly supported by structural evidence from cryo-ET of mouse sperm
      flagella (PMID:37865089). Also consistent with UniProt subcellular location
      annotation.
    supported_by:
    - reference_id: PMID:37865089
      supporting_text: "in situ cryoET and subtomogram averaging has achieved up to\
        \ 6.0 Å reconstructions of native microtubule structures in mouse and human\
        \ sperm samples"
- term:
    id: GO:0005929
    label: cilium
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: Alpha-tubulin is a component of ciliary microtubules. Consistent with
      the UniProt annotation showing flagellum axoneme localization and Reactome pathways
      for cilium assembly.
    action: ACCEPT
    reason: Supported by the broader literature on tubulin in cilia and flagella,
      and by Reactome pathways (R-MMU-5617833 Cilium Assembly).
- term:
    id: GO:0015630
    label: microtubule cytoskeleton
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: Alpha-tubulin is a fundamental component of the microtubule cytoskeleton.
    action: ACCEPT
    reason: Core localization. Well established for all alpha-tubulins.
- term:
    id: GO:0036464
    label: cytoplasmic ribonucleoprotein granule
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: This annotation suggests Tuba1a localizes to cytoplasmic ribonucleoprotein
      granules. While microtubules are involved in transport and localization of RNP
      granules, the evidence for Tuba1a being a resident component of these granules
      is not strong.
    action: MARK_AS_OVER_ANNOTATED
    reason: This is likely a high-throughput proteomics-based annotation transferred
      from the human ortholog. While microtubules transport RNP granules, tubulin
      itself is not a functional component of RNP granules; it is a component of the
      microtubule tracks these granules travel on.
- term:
    id: GO:0042802
    label: identical protein binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: Alpha-tubulin can form lateral contacts with other alpha-tubulin subunits
      within the microtubule lattice. This is a consequence of its role in microtubule
      polymerization.
    action: KEEP_AS_NON_CORE
    reason: While alpha-tubulin does make lateral contacts with itself in the microtubule
      lattice, the primary functional interaction is heterodimer formation with beta-tubulin
      (protein heterodimerization activity). Identical protein binding is a secondary
      consequence of microtubule structure, not a primary function.
- term:
    id: GO:0055037
    label: recycling endosome
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: This annotation suggests Tuba1a localizes to recycling endosomes. This
      is likely from proteomics experiments where tubulin was detected in endosome-enriched
      fractions.
    action: MARK_AS_OVER_ANNOTATED
    reason: Tubulin is highly abundant and can be detected in many subcellular fractions.
      Microtubules provide tracks for recycling endosome transport, but tubulin is
      not a bona fide component of the recycling endosome itself. This is a common
      over-annotation for abundant cytoskeletal proteins.
# ============================================================
# IMP annotation (PMID:20603323) - microtubule plus-end
# ============================================================
- term:
    id: GO:0035371
    label: microtubule plus-end
  evidence_type: IMP
  original_reference_id: PMID:20603323
  review:
    summary: PMID:20603323 examined disease-associated TUBA1A mutations and showed
      suppression of microtubule growth rate in neurites. Newly incorporated tubulin
      dimers are added at the plus-end of microtubules.
    action: ACCEPT
    reason: Alpha-tubulin is incorporated at the microtubule plus-end during polymerization.
      This is a well-established localization for newly assembled tubulin.
    supported_by:
    - reference_id: PMID:20603323
      supporting_text: "a suppression of microtubule growth rate in the neurites (but\
        \ not the soma) of cultured neurons"
# ============================================================
# ISO annotations (GO_REF:0000119)
# ============================================================
- term:
    id: GO:0005874
    label: microtubule
  evidence_type: ISO
  original_reference_id: GO_REF:0000119
  review:
    summary: ISO annotation for microtubule localization, consistent with IBA annotation.
      Core localization.
    action: ACCEPT
    reason: Redundant with IBA but correct. Core localization.
- term:
    id: GO:0005879
    label: axonemal microtubule
  evidence_type: ISO
  original_reference_id: GO_REF:0000119
  review:
    summary: ISO annotation for axonemal microtubule localization. Directly supported
      by cryo-ET of mouse sperm flagella (PMID:37865089).
    action: ACCEPT
    reason: Correct. Directly confirmed by PMID:37865089.
- term:
    id: GO:0005929
    label: cilium
  evidence_type: ISO
  original_reference_id: GO_REF:0000119
  review:
    summary: ISO annotation for cilium localization. Consistent with the known role
      of alpha-tubulin in cilia and flagella.
    action: ACCEPT
    reason: Correct. Consistent with flagellum localization shown in PMID:37865089.
- term:
    id: GO:0015630
    label: microtubule cytoskeleton
  evidence_type: ISO
  original_reference_id: GO_REF:0000119
  review:
    summary: ISO annotation for microtubule cytoskeleton. Core localization.
    action: ACCEPT
    reason: Correct. Redundant with IEA but well established.
- term:
    id: GO:0036464
    label: cytoplasmic ribonucleoprotein granule
  evidence_type: ISO
  original_reference_id: GO_REF:0000119
  review:
    summary: ISO annotation for RNP granule localization. Same concern as the IEA
      annotation.
    action: MARK_AS_OVER_ANNOTATED
    reason: Same issue as the IEA annotation. Tubulin is not a bona fide component
      of RNP granules. Likely an artifact of proteomic co-purification due to tubulin
      abundance.
- term:
    id: GO:0042802
    label: identical protein binding
  evidence_type: ISO
  original_reference_id: GO_REF:0000119
  review:
    summary: ISO annotation for identical protein binding. Same assessment as the
      IEA annotation.
    action: KEEP_AS_NON_CORE
    reason: Technically true due to lateral contacts in the microtubule lattice, but
      not a primary functional activity. The core interaction is heterodimerization
      with beta-tubulin.
- term:
    id: GO:0055037
    label: recycling endosome
  evidence_type: ISO
  original_reference_id: GO_REF:0000119
  review:
    summary: ISO annotation for recycling endosome localization. Same concern as the
      IEA annotation.
    action: MARK_AS_OVER_ANNOTATED
    reason: Tubulin is not a resident component of recycling endosomes. Likely over-annotation
      from proteomics data.
# ============================================================
# ISO annotations (GO_REF:0000096)
# ============================================================
- term:
    id: GO:0019904
    label: protein domain specific binding
  evidence_type: ISO
  original_reference_id: GO_REF:0000096
  review:
    summary: This annotation suggests Tuba1a has protein domain specific binding activity.
      Alpha-tubulin interacts with various MAPs and motors through specific domain
      interactions.
    action: KEEP_AS_NON_CORE
    reason: Alpha-tubulin does interact with specific protein domains (e.g., CAP-Gly
      domains of CYLD, CLIP proteins), but this is a generic term. Not a core molecular
      function annotation.
- term:
    id: GO:0043209
    label: myelin sheath
  evidence_type: ISO
  original_reference_id: GO_REF:0000096
  review:
    summary: ISO annotation for myelin sheath localization. Consistent with the HDA
      annotation from PMID:17634366 showing tubulin in purified myelin membranes.
    action: KEEP_AS_NON_CORE
    reason: Tubulin has been detected in myelin proteomics studies (PMID:17634366),
      but this likely reflects cytoskeletal contamination of myelin preparations or
      microtubule tracks within myelin-forming oligodendrocyte processes. Not a core
      localization.
- term:
    id: GO:0045121
    label: membrane raft
  evidence_type: ISO
  original_reference_id: GO_REF:0000096
  review:
    summary: This annotation suggests Tuba1a localizes to membrane rafts. Tubulin
      has been detected in detergent-resistant membrane fractions in some proteomics
      studies.
    action: MARK_AS_OVER_ANNOTATED
    reason: Tubulin is one of the most abundant cellular proteins and is frequently
      detected in membrane raft preparations. This likely represents non-specific
      association or contamination rather than bona fide localization to membrane
      rafts.
# ============================================================
# IDA annotations (PMID:37865089) - sperm flagellum
# ============================================================
- term:
    id: GO:0030317
    label: flagellated sperm motility
  evidence_type: IDA
  original_reference_id: PMID:37865089
  review:
    summary: PMID:37865089 identified Tuba1a as a component of sperm flagellar doublet
      microtubules using cryo-ET and AlphaFold2 docking. Tubulin is essential for
      flagellar assembly and motility.
    action: KEEP_AS_NON_CORE
    reason: Tuba1a is a component of sperm flagellar microtubules, but its role in
      sperm motility is as a structural component rather than a regulatory one. This
      is a non-core function compared to its primary neuronal roles. The annotation
      is valid but represents a secondary tissue-specific function.
    supported_by:
    - reference_id: PMID:37865089
      supporting_text: "in situ cryoET and subtomogram averaging has achieved up to\
        \ 6.0 Å reconstructions of native microtubule structures in mouse and human\
        \ sperm samples"
- term:
    id: GO:0036126
    label: sperm flagellum
  evidence_type: IDA
  original_reference_id: PMID:37865089
  review:
    summary: PMID:37865089 directly identified Tuba1a in sperm flagellar doublet microtubules
      by cryo-ET structure determination at 7.7 angstrom resolution.
    action: ACCEPT
    reason: Directly demonstrated by structural biology (cryo-ET). Tuba1a is a component
      of sperm flagellar doublet microtubules.
    supported_by:
    - reference_id: PMID:37865089
      supporting_text: "in situ cryoET and subtomogram averaging has achieved up to\
        \ 6.0 Å reconstructions of native microtubule structures in mouse and human\
        \ sperm samples"
# ============================================================
# IMP/IDA annotations (PMID:26658218) - neuromuscular junction
# ============================================================
- term:
    id: GO:0031594
    label: neuromuscular junction
  evidence_type: IMP
  original_reference_id: PMID:26658218
  review:
    summary: PMID:26658218 showed that Tuba1a mutant mice (ND allele) have motor neuron
      synapse defects at the neuromuscular junction. Homozygous mutants showed failure
      of motor neurons to innervate target muscles.
    action: KEEP_AS_NON_CORE
    reason: Tuba1a is localized to the NMJ as part of the microtubule cytoskeleton
      in motor neuron axon terminals. The defects in NMJ are secondary to its role
      in microtubule-based transport and synapse maintenance.
    supported_by:
    - reference_id: PMID:26658218
      supporting_text: "Motor neurons fail to innervate target muscles in the limbs\
        \ and show synapse defects at proximal targets"
- term:
    id: GO:0031594
    label: neuromuscular junction
  evidence_type: IDA
  original_reference_id: PMID:26658218
  review:
    summary: IDA annotation indicating Tuba1a is detected at the neuromuscular junction.
      This is consistent with the IMP annotation from the same paper.
    action: KEEP_AS_NON_CORE
    reason: Tuba1a is present at the NMJ as part of the microtubule cytoskeleton but
      this is a secondary localization.
    supported_by:
    - reference_id: PMID:26658218
      supporting_text: "Motor neurons fail to innervate target muscles in the limbs\
        \ and show synapse defects at proximal targets"
- term:
    id: GO:0050807
    label: regulation of synapse organization
  evidence_type: IMP
  original_reference_id: PMID:26658218
  review:
    summary: PMID:26658218 demonstrated that Tuba1a ND mutation leads to synapse defects
      at the NMJ. The study also showed NMJ size reduction over time in heterozygous
      mutants (PMID:32184299).
    action: KEEP_AS_NON_CORE
    reason: Tuba1a contributes to synapse organization through its role in microtubule-based
      transport and cytoskeletal integrity, but this is a downstream consequence rather
      than a direct regulatory function. The synapse defects are secondary to general
      microtubule dysfunction.
    supported_by:
    - reference_id: PMID:26658218
      supporting_text: "Motor neurons fail to innervate target muscles in the limbs\
        \ and show synapse defects at proximal targets"
- term:
    id: GO:0050807
    label: regulation of synapse organization
  evidence_type: IDA
  original_reference_id: PMID:26658218
  review:
    summary: IDA annotation for regulation of synapse organization from the same paper
      as the IMP annotation.
    action: KEEP_AS_NON_CORE
    reason: Same rationale as the IMP annotation. Synapse organization effects are
      secondary to microtubule dysfunction.
# ============================================================
# IMP annotations (PMID:22101068) - Rgsc1736 mutant
# ============================================================
- term:
    id: GO:0000226
    label: microtubule cytoskeleton organization
  evidence_type: IMP
  original_reference_id: PMID:22101068
  review:
    summary: PMID:22101068 describes a novel ENU-induced Tuba1a mutant (D263G) with
      abnormal brain morphology indicating disrupted microtubule organization during
      development.
    action: ACCEPT
    reason: Core function. The D263G mutation in Tuba1a disrupts microtubule cytoskeleton
      organization, consistent with the S140G allele (PMID:17218254).
    supported_by:
    - reference_id: PMID:22101068
      supporting_text: "We identified a missense mutation in the Tuba1 gene, which\
        \ encodes the TUBA1 protein, and designated the mutant gene Tuba1(Rgsc1736).\
        \ This mutation results in an aspartic acid to glycine substitution in the\
        \ TUBA1 protein."
- term:
    id: GO:0007626
    label: locomotory behavior
  evidence_type: IMP
  original_reference_id: PMID:22101068
  review:
    summary: PMID:22101068 showed the Tuba1a Rgsc1736 mutant has significantly increased
      spontaneous locomotor activity, consistent with the hyperactive Jenna mutant
      (PMID:17218254).
    action: KEEP_AS_NON_CORE
    reason: Locomotory behavior defects are downstream consequences of impaired neuronal
      migration and brain malformation, not a direct function of Tuba1a. This is a
      phenotypic readout of Tuba1a mutation rather than a function.
    supported_by:
    - reference_id: PMID:22101068
      supporting_text: "exhibited a significant increase in spontaneous locomotor\
        \ activity"
- term:
    id: GO:0021859
    label: pyramidal neuron differentiation
  evidence_type: IMP
  original_reference_id: PMID:22101068
  review:
    summary: PMID:22101068 and PMID:17218254 both show disrupted pyramidal cell layers
      in the hippocampus of Tuba1a mutant mice, indicating a role in pyramidal neuron
      differentiation.
    action: KEEP_AS_NON_CORE
    reason: The pyramidal neuron phenotype is a consequence of impaired neuronal migration
      rather than a specific role in pyramidal neuron differentiation per se. The
      defect is in migration not differentiation fate determination.
    supported_by:
    - reference_id: PMID:17218254
      supporting_text: "Staining with cresyl violet and with the neuronal marker NeuN\
        \ showed hippocampal disorganization with an additional layer of pyramidal\
        \ cells in the stratum oriens"
- term:
    id: GO:0021987
    label: cerebral cortex development
  evidence_type: IMP
  original_reference_id: PMID:22101068
  review:
    summary: PMID:22101068 showed cortical abnormalities in the Tuba1a Rgsc1736 mutant.
      PMID:17218254 showed wave-like perturbations in cortical layers II/III and IV
      in the Jenna mutant.
    action: KEEP_AS_NON_CORE
    reason: Cerebral cortex development is affected by Tuba1a mutations, but this
      is a downstream phenotypic consequence of impaired neuronal migration. The core
      function is microtubule-based neuronal migration, which then impacts cortical
      development.
    supported_by:
    - reference_id: PMID:17218254
      supporting_text: "closer examination of NeuN, Cux-1, and Nissl stains revealed\
        \ wave-like perturbations in layer IV"
- term:
    id: GO:0035641
    label: locomotory exploration behavior
  evidence_type: IMP
  original_reference_id: PMID:22101068
  review:
    summary: PMID:22101068 showed the mutant exhibited abnormal open-field behavior
      and inattention to novel objects, which relates to locomotory exploration.
    action: KEEP_AS_NON_CORE
    reason: Behavioral phenotype is a distal consequence of brain malformation caused
      by Tuba1a mutation. Not a direct function.
    supported_by:
    - reference_id: PMID:22101068
      supporting_text: "Tuba1(Rgsc1736) heterozygotes exhibited inattention to novel\
        \ objects and aberrant patterns of home-cage activity"
# ============================================================
# IMP annotations (PMID:32184299) - reduced TUBA1A trafficking
# ============================================================
- term:
    id: GO:0006886
    label: intracellular protein transport
  evidence_type: IMP
  original_reference_id: PMID:32184299
  review:
    summary: PMID:32184299 showed that reduced TUBA1A results in fewer microtubule
      tracks in axons, leading to more pausing during organelle trafficking. Trafficking
      defects impair synaptic maintenance.
    action: KEEP_AS_NON_CORE
    reason: Tuba1a contributes to intracellular transport by providing microtubule
      tracks for motor protein-based transport. The trafficking defect is secondary
      to reduced microtubule assembly. This is a downstream consequence of Tuba1a's
      structural role.
    supported_by:
    - reference_id: PMID:32184299
      supporting_text: "reduced TUBA1A allows for assembly of less microtubules in\
        \ axons resulting in more pausing during organelle trafficking"
- term:
    id: GO:0046785
    label: microtubule polymerization
  evidence_type: IMP
  original_reference_id: PMID:32184299
  review:
    summary: PMID:32184299 showed reduced microtubule assembly in axons of Tuba1a
      ND mutant neurons. Alpha-tubulin is the building block for microtubule polymerization.
    action: ACCEPT
    reason: Core function. Alpha-tubulin heterodimers are the direct subunits that
      polymerize to form microtubules. Reduced Tuba1a leads directly to fewer microtubules.
    supported_by:
    - reference_id: PMID:32184299
      supporting_text: "reduced TUBA1A allows for assembly of less microtubules in\
        \ axons"
- term:
    id: GO:0050808
    label: synapse organization
  evidence_type: IMP
  original_reference_id: PMID:32184299
  review:
    summary: PMID:32184299 showed Tuba1a ND heterozygous mice develop age-related
      NMJ synapse size reduction, demonstrating a role in synapse maintenance/organization.
    action: KEEP_AS_NON_CORE
    reason: Synapse organization defects are downstream of microtubule-based transport
      deficits. The NMJ synapse deterioration is secondary to reduced microtubule
      tracks for trafficking.
    supported_by:
    - reference_id: PMID:32184299
      supporting_text: "However, NMJ synapse morphology and animal behavior deteriorate\
        \ in an age-related manner in Tuba1aND/+animals, without evidence of neuronal\
        \ cell death or degeneration"
- term:
    id: GO:0061744
    label: motor behavior
  evidence_type: IMP
  original_reference_id: PMID:32184299
  review:
    summary: PMID:32184299 showed Tuba1a ND heterozygous mice develop adult-onset
      ataxia. Motor behavior deficits are a phenotypic consequence of synaptic and
      trafficking defects.
    action: KEEP_AS_NON_CORE
    reason: Motor behavior deficits are a distal phenotypic consequence of Tuba1a
      mutation, not a direct function. Behavioral phenotypes should be kept as non-core.
    supported_by:
    - reference_id: PMID:32184299
      supporting_text: "Tuba1aND/+ mice develop adult-onset ataxia"
- term:
    id: GO:0072384
    label: organelle transport along microtubule
  evidence_type: IMP
  original_reference_id: PMID:32184299
  review:
    summary: PMID:32184299 showed trafficking defects with more pausing during organelle
      transport in Tuba1a ND neurons due to insufficient microtubule tracks.
    action: KEEP_AS_NON_CORE
    reason: Tuba1a provides the microtubule tracks for organelle transport. The transport
      defects are secondary to reduced microtubule assembly. Not a direct function
      of Tuba1a but a consequence of its structural role.
    supported_by:
    - reference_id: PMID:32184299
      supporting_text: "reduced TUBA1A allows for assembly of less microtubules in\
        \ axons resulting in more pausing during organelle trafficking"
# ============================================================
# IMP annotations (PMID:28687665) - straighter microtubules
# ============================================================
- term:
    id: GO:0000226
    label: microtubule cytoskeleton organization
  evidence_type: IMP
  original_reference_id: PMID:28687665
  review:
    summary: PMID:28687665 showed the S140G mutation leads to increased straightness
      of newly polymerized microtubules and altered conformational properties of the
      alpha/beta heterodimer.
    action: ACCEPT
    reason: Core function. Directly demonstrates the role of Tuba1a in microtubule
      cytoskeleton organization through its effect on microtubule geometry and dynamics.
    supported_by:
    - reference_id: PMID:28687665
      supporting_text: "Tuba1a mutation led to increased straightness of newly polymerized\
        \ MTs, and structural modeling data suggest a conformational change in the\
        \ alpha/beta-tubulin heterodimer"
- term:
    id: GO:0001764
    label: neuron migration
  evidence_type: IMP
  original_reference_id: PMID:28687665
  review:
    summary: PMID:28687665 showed slowed neuronal migration and increased branching
      in Tuba1a S140G mutant neurons by live imaging. Neurons accumulated along the
      rostral migratory stream.
    action: ACCEPT
    reason: Core function. Neuron migration is the most well-established and specific
      phenotype of Tuba1a mutations across multiple independent alleles and studies.
      This is the defining function of Tuba1a in brain development.
    supported_by:
    - reference_id: PMID:28687665
      supporting_text: "Live imaging of Tuba1a-mutant neurons revealed slowed migration\
        \ and increased neuronal branching, which correlated with directionality alterations\
        \ and perturbed nucleus-centrosome (N-C) coupling"
- term:
    id: GO:0001764
    label: neuron migration
  evidence_type: IMP
  original_reference_id: PMID:31386652
  review:
    summary: PMID:31386652 generated Tuba1a knockout mice and showed perinatal lethality
      with significant forebrain dysmorphology due to migration defects.
    action: ACCEPT
    reason: Core function. The null allele confirms the essential, non-redundant role
      of Tuba1a in neuronal migration.
    supported_by:
    - reference_id: PMID:31386652
      supporting_text: "loss of Tuba1a is perinatal lethal and leads to significant\
        \ forebrain dysmorphology"
- term:
    id: GO:0007098
    label: centrosome cycle
  evidence_type: IMP
  original_reference_id: PMID:28687665
  review:
    summary: PMID:28687665 showed perturbed nucleus-centrosome coupling in Tuba1a
      S140G mutant neurons, which is relevant to the centrosome cycle during neuronal
      migration.
    action: KEEP_AS_NON_CORE
    reason: The centrosome coupling defect is a consequence of altered microtubule
      properties rather than a direct role in centrosome cycle regulation. The annotation
      is somewhat overspecific.
    supported_by:
    - reference_id: PMID:28687665
      supporting_text: "perturbed nucleus-centrosome (N-C) coupling"
- term:
    id: GO:0010001
    label: glial cell differentiation
  evidence_type: IMP
  original_reference_id: PMID:28687665
  review:
    summary: PMID:28687665 showed that glial cells are dispersed along the rostral
      migratory stream in Tuba1a S140G mutants.
    action: KEEP_AS_NON_CORE
    reason: The glial cell dispersion is likely secondary to disrupted migration rather
      than a specific role in glial cell differentiation. Microtubules are broadly
      required in all cell types.
    supported_by:
    - reference_id: PMID:28687665
      supporting_text: "glial cells are dispersed along the rostral migratory stream\
        \ in postnatal and adult brains"
- term:
    id: GO:0010467
    label: gene expression
  evidence_type: IMP
  original_reference_id: PMID:31386652
  review:
    summary: PMID:31386652 examined differential requirements of tubulin genes in
      forebrain development. The annotation to gene expression is very broad and likely
      relates to indirect effects of Tuba1a loss on downstream gene expression patterns.
    action: MARK_AS_OVER_ANNOTATED
    reason: Gene expression is an extremely broad term. Tuba1a is not a transcription
      factor or transcriptional regulator. Any effects on gene expression are indirect,
      downstream consequences of disrupted microtubule-dependent signaling or altered
      cellular state due to loss of Tuba1a. This is over-annotation.
- term:
    id: GO:0021987
    label: cerebral cortex development
  evidence_type: IMP
  original_reference_id: PMID:31386652
  review:
    summary: PMID:31386652 showed Tuba1a null mice have significant forebrain dysmorphology.
      Also shown in multiple other Tuba1a mutant studies.
    action: KEEP_AS_NON_CORE
    reason: Valid phenotype but cerebral cortex development is a downstream consequence
      of Tuba1a's role in neuronal migration. Keep as non-core.
    supported_by:
    - reference_id: PMID:31386652
      supporting_text: "loss of Tuba1a is perinatal lethal and leads to significant\
        \ forebrain dysmorphology"
- term:
    id: GO:0022008
    label: neurogenesis
  evidence_type: IMP
  original_reference_id: PMID:31386652
  review:
    summary: PMID:31386652 showed defects in forebrain neurogenesis in Tuba1a null
      mice. Consistent with the essential role in neuronal development.
    action: KEEP_AS_NON_CORE
    reason: Neurogenesis is a broad parent term. The specific function of Tuba1a is
      in neuron migration rather than neurogenesis per se. The neurogenesis annotation
      from PMID:21041996 showed normal neurogenic potential but ectopic positioning,
      confirming that the problem is migration, not generation of neurons.
    supported_by:
    - reference_id: PMID:21041996
      supporting_text: "mice harbouring an S140G mutation in Tuba1a present with normal\
        \ neurogenic potential, but that this neurogenesis is often ectopic"
- term:
    id: GO:0030182
    label: neuron differentiation
  evidence_type: IMP
  original_reference_id: PMID:28687665
  review:
    summary: PMID:28687665 showed defects in neuronal migration and branching in Tuba1a
      S140G mutant, which affects neuron differentiation.
    action: KEEP_AS_NON_CORE
    reason: The evidence supports altered migration and branching in mutant neurons.
      This is consistent with neuronal morphogenesis but is broader than the most
      precise supported process, neuron migration, so it should be retained as non-core.
    supported_by:
    - reference_id: PMID:28687665
      supporting_text: "our work shows that Tuba1a plays an essential, noncompensated\
        \ role in neuronal saltatory migration in vivo"
- term:
    id: GO:0046785
    label: microtubule polymerization
  evidence_type: IMP
  original_reference_id: PMID:28687665
  review:
    summary: PMID:28687665 showed altered microtubule polymerization properties (increased
      straightness) in Tuba1a S140G mutant neurons.
    action: ACCEPT
    reason: Core function. Tuba1a heterodimers are the building blocks for microtubule
      polymerization. The S140G mutation directly alters polymerization properties.
    supported_by:
    - reference_id: PMID:28687665
      supporting_text: "Tuba1a mutation led to increased straightness of newly polymerized\
        \ MTs"
- term:
    id: GO:0048853
    label: forebrain morphogenesis
  evidence_type: IMP
  original_reference_id: PMID:31386652
  review:
    summary: PMID:31386652 showed Tuba1a null mice have significant forebrain dysmorphology
      with perinatal lethality.
    action: KEEP_AS_NON_CORE
    reason: Forebrain morphogenesis defects are a downstream consequence of impaired
      neuronal migration. Keep as non-core.
    supported_by:
    - reference_id: PMID:31386652
      supporting_text: "loss of Tuba1a is perinatal lethal and leads to significant\
        \ forebrain dysmorphology"
- term:
    id: GO:0140058
    label: neuron projection arborization
  evidence_type: IMP
  original_reference_id: PMID:28687665
  review:
    summary: PMID:28687665 showed increased neuronal branching in Tuba1a S140G mutant
      neurons during migration by live imaging.
    action: KEEP_AS_NON_CORE
    reason: Increased branching is observed in Tuba1a mutant neurons but this reflects
      altered microtubule dynamics rather than a direct role in arborization regulation.
      Keep as non-core.
    supported_by:
    - reference_id: PMID:28687665
      supporting_text: "Live imaging of Tuba1a-mutant neurons revealed slowed migration\
        \ and increased neuronal branching"
# ============================================================
# IMP annotation (PMID:21041996) - hippocampal neurogenesis
# ============================================================
- term:
    id: GO:0001764
    label: neuron migration
  evidence_type: IMP
  original_reference_id: PMID:21041996
  review:
    summary: PMID:21041996 showed that S140G mutant mice have defective migration
      of neurons in the dentate gyrus, with normal neurogenic potential but ectopic
      positioning.
    action: ACCEPT
    reason: Core function. This study specifically demonstrated that the neurogenesis
      is normal but migration is defective in Tuba1a mutant hippocampus.
    supported_by:
    - reference_id: PMID:21041996
      supporting_text: "mice harbouring an S140G mutation in Tuba1a present with normal\
        \ neurogenic potential, but that this neurogenesis is often ectopic. Morphological\
        \ analysis of the dentate gyrus in adulthood revealed a disorganised subgranular\
        \ zone and a dispersed granule cell layer."
# ============================================================
# IDA annotations (PMID:27793670) - hedgehog signaling
# ============================================================
- term:
    id: GO:0007224
    label: smoothened signaling pathway
  evidence_type: IDA
  original_reference_id: PMID:27793670
  review:
    summary: PMID:27793670 showed that Hh pathway activation increases microtubule
      acetylation via Smoothened in MEFs. Tubulin acetylation is a downstream readout,
      not an active participant in Smo signaling.
    action: MARK_AS_OVER_ANNOTATED
    reason: Tuba1a is a substrate of acetylation downstream of Smo signaling, not
      an active participant in the smoothened signaling pathway. The study shows that
      Smo promotes tubulin acetylation, meaning tubulin is a downstream target/substrate,
      not a signaling component. This is over-annotation.
    supported_by:
    - reference_id: PMID:27793670
      supporting_text: "Hh pathway activation in mouse embryonic fibroblast cells\
        \ (MEFs) increases microtubule acetylation via smoothened (Smo)"
- term:
    id: GO:0071277
    label: cellular response to calcium ion
  evidence_type: IDA
  original_reference_id: PMID:27793670
  review:
    summary: PMID:27793670 showed that intracellular calcium increase is important
      for Hh-dependent tubulin acetylation downstream of Smo. Again, tubulin is a
      downstream substrate modified in response to calcium.
    action: MARK_AS_OVER_ANNOTATED
    reason: Tubulin acetylation occurs in response to calcium signaling downstream
      of Smo, but tubulin itself is not responding to calcium in any direct sense.
      It is a substrate that gets modified. This is over-annotation of a passive substrate.
    supported_by:
    - reference_id: PMID:27793670
      supporting_text: "an increase in intracellular calcium is important for Hh-dependent\
        \ tubulin acetylation at the downstream of Smo"
# ============================================================
# IMP annotation (PMID:27976998) - mechanical stimulus
# ============================================================
- term:
    id: GO:0009612
    label: response to mechanical stimulus
  evidence_type: IMP
  original_reference_id: PMID:27976998
  review:
    summary: PMID:27976998 showed that mice lacking Atat1 (the alpha-tubulin acetyltransferase)
      in sensory neurons have profound deficits in mechanosensitivity. Acetylated
      tubulin at K40 is essential for touch sensation by maintaining cellular stiffness.
    action: KEEP_AS_NON_CORE
    reason: The study demonstrates that tubulin acetylation (which occurs on alpha-tubulin
      K40) is essential for mechanosensitivity. However, the annotation is to Tuba1a
      specifically when the study used Atat1 knockout mice. The mechanosensitivity
      role is for acetylated alpha-tubulin generally, not Tuba1a specifically. Keep
      as non-core since alpha-tubulin acetylation is important for touch but may involve
      multiple alpha-tubulin isotypes.
    supported_by:
    - reference_id: PMID:27976998
      supporting_text: "mice lacking the alpha-tubulin acetyltransferase Atat1 in\
        \ sensory neurons display profound deficits in their ability to detect mechanical\
        \ stimuli"
# ============================================================
# IMP annotations (PMID:21041996) - dentate gyrus
# ============================================================
- term:
    id: GO:0021542
    label: dentate gyrus development
  evidence_type: IMP
  original_reference_id: PMID:21041996
  review:
    summary: PMID:21041996 showed the Tuba1a S140G mutant has a disorganized subgranular
      zone and dispersed granule cell layer in the dentate gyrus due to defective
      migration.
    action: KEEP_AS_NON_CORE
    reason: Dentate gyrus development defects are a downstream consequence of impaired
      neuronal migration in the hippocampus. Keep as non-core.
    supported_by:
    - reference_id: PMID:21041996
      supporting_text: "Morphological analysis of the dentate gyrus in adulthood revealed\
        \ a disorganised subgranular zone and a dispersed granule cell layer"
- term:
    id: GO:0022008
    label: neurogenesis
  evidence_type: IMP
  original_reference_id: PMID:21041996
  review:
    summary: PMID:21041996 explicitly showed normal neurogenic potential but ectopic
      neurogenesis in Tuba1a mutant mice.
    action: KEEP_AS_NON_CORE
    reason: The study showed neurogenic potential is normal but positioning is ectopic.
      The core function is migration, not neurogenesis. This annotation should be
      kept as non-core since the defect is in migration of newly generated neurons,
      not in neurogenesis itself.
    supported_by:
    - reference_id: PMID:21041996
      supporting_text: "mice harbouring an S140G mutation in Tuba1a present with normal\
        \ neurogenic potential, but that this neurogenesis is often ectopic"
# ============================================================
# IMP annotations (PMID:21875651) - superior colliculus
# ============================================================
- term:
    id: GO:0000226
    label: microtubule cytoskeleton organization
  evidence_type: IMP
  original_reference_id: PMID:21875651
  review:
    summary: PMID:21875651 showed that the S140G mutation impairs radial migration
      of neurons in the superior colliculus, leading to thinning and apparent layer
      fusion due to microtubule dysfunction.
    action: ACCEPT
    reason: Core function. Consistent with the IBA and other IMP annotations for microtubule
      cytoskeleton organization.
    supported_by:
    - reference_id: PMID:21875651
      supporting_text: "The Jenna mutant mouse harbours an S140G mutation in Tuba1a\
        \ that impairs tubulin heterodimer formation resulting in defective neuronal\
        \ migration during development"
- term:
    id: GO:0000793
    label: condensed chromosome
  evidence_type: IDA
  original_reference_id: PMID:24244602
  review:
    summary: PMID:24244602 showed TFIIB co-localizes with alpha-tubulin on condensed
      chromosomes during oocyte meiosis. Alpha-tubulin is part of the spindle that
      interacts with condensed chromosomes.
    action: KEEP_AS_NON_CORE
    reason: The study primarily concerns TFIIB localization. Alpha-tubulin is present
      at the spindle near condensed chromosomes during meiosis, but is not a component
      of the condensed chromosome itself. The annotation may be slightly misleading
      but reflects the mitotic spindle-chromosome interface. Keep as non-core.
    supported_by:
    - reference_id: PMID:24244602
      supporting_text: "After progression to GV breakdown (GVBD), TFIIB and alpha-tubulin\
        \ co-localize and accumulate in the vicinity of the condensed chromosomes"
- term:
    id: GO:0001764
    label: neuron migration
  evidence_type: IMP
  original_reference_id: PMID:21875651
  review:
    summary: PMID:21875651 showed impaired radial migration of neurons in the superior
      colliculus of S140G mutant mice using birthdate labeling at E12.5 and E13.5.
    action: ACCEPT
    reason: Core function. Neuron migration defects in the superior colliculus add
      to the body of evidence across cortex, hippocampus, and RMS that Tuba1a is essential
      for neuronal migration.
    supported_by:
    - reference_id: PMID:21875651
      supporting_text: "the S140G mutation impairs the radial migration of neurons\
        \ in the SC"
- term:
    id: GO:0001964
    label: startle response
  evidence_type: IMP
  original_reference_id: PMID:21875651
  review:
    summary: PMID:21875651 showed Tuba1a S140G mutant mice have an exaggerated acoustic
      startle response, consistent with disrupted superior colliculus cytoarchitecture.
    action: KEEP_AS_NON_CORE
    reason: The startle response phenotype is a distal behavioral consequence of disrupted
      brain cytoarchitecture due to impaired neuronal migration. Not a direct function.
    supported_by:
    - reference_id: PMID:21875651
      supporting_text: "we find that Jenna mutants exhibit an exaggerated acoustic\
        \ startle response"
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:24244602
  review:
    summary: PMID:24244602 showed TFIIB interacts with alpha-tubulin by BiFC and co-localization
      during oocyte meiosis.
    action: MARK_AS_OVER_ANNOTATED
    reason: The TFIIB-alpha-tubulin interaction is supported, but GO:0005515 is too
      generic to be informative for Tuba1a. The paper primarily supports TFIIB association
      with spindle microtubules during oocyte meiosis; it does not establish a distinct
      Tuba1a binding function beyond its microtubule structural role.
    supported_by:
    - reference_id: PMID:24244602
      supporting_text: "co-transfection of BiFC plasmids pHA-Tf2b and pFlag-Tuba1alpha\
        \ further confirms a direct interaction between TFIIB and alpha-tubulins"
- term:
    id: GO:0048873
    label: homeostasis of number of cells within a tissue
  evidence_type: IMP
  original_reference_id: PMID:21875651
  review:
    summary: PMID:21875651 showed a massive reduction in postmitotic neurons in the
      superior colliculus of Tuba1a mutant mice in adulthood, attributed to increased
      apoptotic cell death.
    action: KEEP_AS_NON_CORE
    reason: The neuronal cell number reduction is a downstream consequence of impaired
      migration and subsequent apoptosis. Tuba1a does not directly regulate cell number
      homeostasis.
    supported_by:
    - reference_id: PMID:21875651
      supporting_text: "A quantitative assessment of neuronal number in adulthood\
        \ reveals a massive reduction in postmitotic neurons in mutant animals, which\
        \ we attribute to increased apoptotic cell death"
- term:
    id: GO:0051402
    label: neuron apoptotic process
  evidence_type: IMP
  original_reference_id: PMID:21875651
  review:
    summary: PMID:21875651 showed increased apoptotic cell death in the superior colliculus
      of Tuba1a S140G mutant mice leading to neuronal loss.
    action: KEEP_AS_NON_CORE
    reason: Neuronal apoptosis is a secondary consequence of impaired migration and
      mispositioning, not a direct function of Tuba1a. The apoptosis likely results
      from failure of migrating neurons to reach proper targets.
    supported_by:
    - reference_id: PMID:21875651
      supporting_text: "an elevated rate of cell death leads to a significant loss\
        \ of neurons in the SC of the Jna/+ mouse between postnatal day 21 (P21) and\
        \ 12 weeks of age"
# ============================================================
# IMP/IPI/IDA annotations (PMID:20603323) - tubulin folding
# ============================================================
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:20603323
  review:
    summary: PMID:20603323 examined disease-associated TUBA1A mutations and their
      effects on protein interactions in the tubulin folding pathway, including interactions
      with prefoldin, CCT, and TBCB.
    action: MODIFY
    reason: Protein binding is uninformative. The specific interactions described
      are with chaperones (prefoldin, CCT) and tubulin-specific cofactors (TBCB) in
      the folding pathway. A more specific term would be protein-folding chaperone
      binding, which is already annotated.
    proposed_replacement_terms:
    - id: GO:0051087
      label: protein-folding chaperone binding
    supported_by:
    - reference_id: PMID:20603323
      supporting_text: "These include a defective interaction with the chaperone prefoldin,\
        \ a reduced efficiency in the generation of productive folding intermediates\
        \ as a result of inefficient interaction with the cytosolic chaperonin, CCT"
- term:
    id: GO:0006458
    label: "'de novo' protein folding"
  evidence_type: IMP
  original_reference_id: PMID:20603323
  review:
    summary: PMID:20603323 showed that TUBA1A mutations affect the de novo tubulin
      folding and heterodimer assembly pathway involving CCT, prefoldin, and tubulin-specific
      chaperones TBCA-TBCE.
    action: KEEP_AS_NON_CORE
    reason: Tuba1a is a substrate of the de novo folding pathway, not an active participant
      in the folding process. The folding is performed by chaperones (CCT, prefoldin)
      and tubulin cofactors (TBCA-TBCE). This annotation describes the folding of
      Tuba1a, not a folding activity by Tuba1a.
    supported_by:
    - reference_id: PMID:20603323
      supporting_text: "We show that the expression of all the mutant proteins in\
        \ vitro results in the generation of tubulin heterodimers in varying yield"
- term:
    id: GO:0008017
    label: microtubule binding
  evidence_type: IMP
  original_reference_id: PMID:20603323
  review:
    summary: PMID:20603323 showed that once folded, mutant tubulin heterodimers can
      co-polymerize with microtubules in vitro, demonstrating microtubule binding
      activity.
    action: ACCEPT
    reason: Alpha-tubulin heterodimers bind to existing microtubules during polymerization.
      This is a core molecular function.
    supported_by:
    - reference_id: PMID:20603323
      supporting_text: "the expression of all the mutant proteins in vitro results\
        \ in the generation of tubulin heterodimers in varying yield and that these\
        \ can co-polymerize with microtubules in vitro"
- term:
    id: GO:0046982
    label: protein heterodimerization activity
  evidence_type: IMP
  original_reference_id: PMID:20603323
  review:
    summary: PMID:20603323 directly examined tubulin heterodimer formation and showed
      disease mutations affect the yield of alpha/beta heterodimers through the chaperone-dependent
      folding pathway.
    action: ACCEPT
    reason: Core molecular function. Alpha-tubulin heterodimerizes with beta-tubulin
      to form the fundamental building block of microtubules. This is a defining activity
      of alpha-tubulin.
    supported_by:
    - reference_id: PMID:20603323
      supporting_text: "We show that the expression of all the mutant proteins in\
        \ vitro results in the generation of tubulin heterodimers in varying yield"
- term:
    id: GO:0050821
    label: protein stabilization
  evidence_type: IMP
  original_reference_id: PMID:20603323
  review:
    summary: PMID:20603323 showed that some mutations cause structural instability
      in vitro and diminished stability in vivo. Tuba1a contributes to the stability
      of the tubulin heterodimer.
    action: KEEP_AS_NON_CORE
    reason: The protein stabilization annotation likely refers to the role of GTP
      binding in stabilizing the heterodimer. This is not an active stabilization
      activity but rather a consequence of heterodimer formation. Keep as non-core.
    supported_by:
    - reference_id: PMID:20603323
      supporting_text: "Other defects include structural instability in vitro, diminished\
        \ stability in vivo"
- term:
    id: GO:0051087
    label: protein-folding chaperone binding
  evidence_type: IDA
  original_reference_id: PMID:20603323
  review:
    summary: PMID:20603323 showed direct interactions between TUBA1A and chaperones
      (prefoldin, CCT) and tubulin cofactors (TBCB) using in vitro folding assays.
    action: KEEP_AS_NON_CORE
    reason: Tuba1a interacts with prefoldin, CCT, and tubulin-specific cofactors
      during maturation, and the annotation is valid. It is a biogenesis interaction
      required to produce folded alpha/beta heterodimers rather than the core activity
      of the mature gene product.
    supported_by:
    - reference_id: PMID:20603323
      supporting_text: "These include a defective interaction with the chaperone prefoldin,\
        \ a reduced efficiency in the generation of productive folding intermediates\
        \ as a result of inefficient interaction with the cytosolic chaperonin, CCT,\
        \ and, in several cases, a failure to stably interact with TBCB"
# ============================================================
# IMP annotations (PMID:17218254) - Jenna mutant
# ============================================================
- term:
    id: GO:0001764
    label: neuron migration
  evidence_type: IMP
  original_reference_id: PMID:17218254
  review:
    summary: The foundational paper demonstrating that the Tuba1a S140G mutation causes
      impaired neuronal migration in mice and lissencephaly in humans. BrdU labeling
      showed defective radial migration at E14.5 and E16.5.
    action: ACCEPT
    reason: Core function. This is the seminal paper establishing that Tuba1a is essential
      for neuronal migration. The migration defect was directly demonstrated by BrdU
      birth-dating experiments and confirmed by BAC transgene rescue.
    supported_by:
    - reference_id: PMID:17218254
      supporting_text: "There was no significant difference between littermate controls\
        \ and Jna/+ mutants when BrdU was injected at E12.5 (F[9,189] < 1; P > 0.05),\
        \ however there was a highly significant difference when injected at E14.5\
        \ (F[9,198] = 4.75; P < 0.0001), and at E16.5 (F[9,270] = 13.3; P < 0.0001)"
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:20037577
  review:
    summary: PMID:20037577 showed that HDAC1 nuclear export leads to interaction with
      motor proteins and impaired mitochondrial transport. The connection to alpha-tubulin
      is indirect -- HDAC1 interacts with tubulin-dependent motor proteins.
    action: MARK_AS_OVER_ANNOTATED
    reason: The study identifies alpha-tubulin in pathological HDAC1/motor-protein
      complexes during axonal damage, but GO:0005515 is too generic and the finding
      is context-dependent rather than a core Tuba1a activity. The more informative
      biology is impaired microtubule-based mitochondrial transport under injury
      conditions.
    supported_by:
    - reference_id: PMID:20037577
      supporting_text: "The formation of complexes between exported HDAC1 and members\
        \ of the kinesin family of motor proteins hindered the interaction with cargo\
        \ molecules"
- term:
    id: GO:0005525
    label: GTP binding
  evidence_type: IMP
  original_reference_id: PMID:17218254
  review:
    summary: PMID:17218254 directly demonstrated that the S140G mutation in the GTP
      binding pocket reduces GTP incorporation by approximately 5-fold using in vitro
      folding assays with alpha-32P-GTP.
    action: ACCEPT
    reason: Core molecular function. Directly demonstrated by biochemical assays showing
      the S140G mutation in the GTP binding N-site reduces GTP binding.
    supported_by:
    - reference_id: PMID:17218254
      supporting_text: "We found that the S140G mutation decreased the ability of\
        \ CCT bound quasi-native alpha-tubulin folding intermediates to incorporate\
        \ GTP by approximately 5-fold"
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: IDA
  original_reference_id: PMID:19056362
  review:
    summary: PMID:19056362 showed tubulin forms a high molecular weight complex with
      PKA RI subunit mainly in the cytosol, then transported to synapses.
    action: ACCEPT
    reason: Correct localization. Tubulin heterodimers are present in the cytosol
      before assembly into microtubules. Consistent with general tubulin biology.
    supported_by:
    - reference_id: PMID:19056362
      supporting_text: "The enrichment of the endogenous HMWC by subcellular fractionation\
        \ and its synthesis in vitro indicate that it is mainly produced in the cytosol,\
        \ and then transported to the synapses"
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: IDA
  original_reference_id: PMID:19056362
  review:
    summary: PMID:19056362 showed PKA RI co-localized with tubulin discretely at the
      cell membrane in COS-7 cells.
    action: KEEP_AS_NON_CORE
    reason: Microtubules extend to the cell periphery and interact with the plasma
      membrane. The plasma membrane localization detected in this study likely reflects
      microtubules near the membrane or tubulin-PKA complexes at the membrane. Keep
      as non-core since this is not the primary localization.
    supported_by:
    - reference_id: PMID:19056362
      supporting_text: "In mouse brain RI co-localized with tubulin in neuropils and\
        \ in COS-7 cells discretely at the cell membrane"
- term:
    id: GO:0007613
    label: memory
  evidence_type: IMP
  original_reference_id: PMID:17218254
  review:
    summary: PMID:17218254 showed Tuba1a S140G mutant mice have impaired spatial working
      memory assessed by T-maze spontaneous and rewarded alternation.
    action: KEEP_AS_NON_CORE
    reason: Memory deficits are a behavioral consequence of disrupted hippocampal
      architecture due to impaired neuronal migration. Not a direct function of Tuba1a.
    supported_by:
    - reference_id: PMID:17218254
      supporting_text: "Jna/+ mice performed significantly worse than littermate controls\
        \ (F[1,12] = 34.1; P < 0.0001) (Figure 5A), alternating just above chance"
- term:
    id: GO:0008344
    label: adult locomotory behavior
  evidence_type: IMP
  original_reference_id: PMID:17218254
  review:
    summary: PMID:17218254 showed Tuba1a S140G mutant mice are hyperactive. BAC transgene
      rescue normalized locomotor behavior.
    action: KEEP_AS_NON_CORE
    reason: Locomotor hyperactivity is a behavioral phenotype resulting from disrupted
      brain cytoarchitecture. Not a direct function. The rescue by BAC transgene confirms
      the phenotype is due to Tuba1a mutation but the behavior is a downstream readout.
    supported_by:
    - reference_id: PMID:17218254
      supporting_text: "A single line that we named Jenna (Jna) was identified with\
        \ a semidominant hyperactive phenotype"
- term:
    id: GO:0008542
    label: visual learning
  evidence_type: IMP
  original_reference_id: PMID:17218254
  review:
    summary: PMID:17218254 tested visual learning-dependent reference memory. However,
      the Tuba1a mutant mice performed well on the visual discrimination task (tactile
      reference memory), showing no deficit in this hippocampal-independent task.
    action: REMOVE
    reason: The study actually showed that Tuba1a S140G mutants can learn a hippocampal-independent
      reference memory task normally. The annotation to "visual learning" appears
      to be an error or over-annotation, as the mutant mice showed NO deficit in this
      task.
    supported_by:
    - reference_id: PMID:17218254
      supporting_text: "Both mutant and control mice were able to learn this task\
        \ (Figure 5C) (F < 1; P > 0.5)"
- term:
    id: GO:0021696
    label: cerebellar cortex morphogenesis
  evidence_type: IMP
  original_reference_id: PMID:17218254
  review:
    summary: PMID:17218254 stated no anatomical abnormalities were seen in the cerebellum
      of Jna/+ mice.
    action: REMOVE
    reason: The paper explicitly states no cerebellar abnormalities were seen in Jna/+
      mice. This annotation appears to be an error.
    supported_by:
    - reference_id: PMID:17218254
      supporting_text: "No anatomical abnormalities were seen in the cerebellum or\
        \ amygdala"
- term:
    id: GO:0021766
    label: hippocampus development
  evidence_type: IMP
  original_reference_id: PMID:17218254
  review:
    summary: PMID:17218254 showed extensive hippocampal disorganization in Tuba1a
      S140G mutant mice, including a fractured pyramidal cell layer and disorganized
      mossy fiber tract.
    action: KEEP_AS_NON_CORE
    reason: Hippocampus development defects are a consequence of impaired neuronal
      migration. The core function is neuron migration. Keep as non-core.
    supported_by:
    - reference_id: PMID:17218254
      supporting_text: "hippocampal disorganization with an additional layer of pyramidal\
        \ cells in the stratum oriens that extended throughout the pyramidal cell\
        \ subfields into the subiculum"
- term:
    id: GO:0030534
    label: adult behavior
  evidence_type: IMP
  original_reference_id: PMID:17218254
  review:
    summary: PMID:17218254 showed multiple behavioral abnormalities including hyperactivity,
      impaired memory, and reduced anxiety in Tuba1a S140G mutant mice.
    action: KEEP_AS_NON_CORE
    reason: Adult behavior is a very broad term. The behavioral phenotypes are downstream
      consequences of brain malformation. Keep as non-core.
- term:
    id: GO:0034612
    label: response to tumor necrosis factor
  evidence_type: IDA
  original_reference_id: PMID:20037577
  review:
    summary: PMID:20037577 showed that TNF-alpha treatment of neurons induces HDAC1
      nuclear export and axonal damage. The study examined the effect on neurons generally,
      and tubulin is a component of the damaged axonal cytoskeleton.
    action: MARK_AS_OVER_ANNOTATED
    reason: Tuba1a is not specifically responding to TNF. The study examined the effect
      of TNF on neurons and found HDAC1 export-dependent axonal damage. Tubulin is
      part of the damaged cytoskeleton but is not an active responder to TNF. This
      is over-annotation of a passive substrate.
    supported_by:
    - reference_id: PMID:20037577
      supporting_text: "cultured neurons exposed to glutamate and tumor necrosis factor-alpha"
- term:
    id: GO:0044877
    label: protein-containing complex binding
  evidence_type: IDA
  original_reference_id: PMID:19056362
  review:
    summary: PMID:19056362 showed alpha/beta-tubulin forms a complex with PKA RI subunit,
      acting as an A kinase anchor protein. This represents binding to a protein-containing
      complex (PKA holoenzyme).
    action: KEEP_AS_NON_CORE
    reason: The study demonstrated that alpha/beta-tubulin can form a complex with
      PKA type I, serving an AKAP-like role. This is a valid but specialized signaling-complex
      interaction and should not be treated as the core function of Tuba1a.
    supported_by:
    - reference_id: PMID:19056362
      supporting_text: "we have determined that the 105 kDa band is a high molecular\
        \ weight complex (HMWC) containing alpha/beta-tubulin and PKA RI"
- term:
    id: GO:0045202
    label: synapse
  evidence_type: IDA
  original_reference_id: PMID:19056362
  review:
    summary: PMID:19056362 showed the tubulin-PKA complex is transported to synapses,
      and PKA RI co-localized with tubulin in neuropils.
    action: KEEP_AS_NON_CORE
    reason: Microtubules extend into synaptic regions and tubulin-PKA complexes are
      transported to synapses. This is a valid but non-core localization for Tuba1a.
    supported_by:
    - reference_id: PMID:19056362
      supporting_text: "it is mainly produced in the cytosol, and then transported\
        \ to the synapses"
- term:
    id: GO:0046982
    label: protein heterodimerization activity
  evidence_type: IMP
  original_reference_id: PMID:17218254
  review:
    summary: PMID:17218254 directly demonstrated that the S140G mutation reduces heterodimer
      formation using in vitro folding assays with 35S-labeled Tuba1a.
    action: ACCEPT
    reason: Core molecular function. Heterodimer formation with beta-tubulin is the
      primary functional activity of alpha-tubulin. Directly demonstrated by biochemical
      assays.
    supported_by:
    - reference_id: PMID:17218254
      supporting_text: "Consistent with the data obtained in our GTP labeling experiments,\
        \ we found that the S140G mutation reduced the efficiency of de novo heterodimer\
        \ formation"
- term:
    id: GO:1902065
    label: response to L-glutamate
  evidence_type: IDA
  original_reference_id: PMID:20037577
  review:
    summary: PMID:20037577 showed that glutamate exposure of neurons induces HDAC1
      nuclear export and impaired mitochondrial transport in axons. Tubulin is part
      of the affected cytoskeleton.
    action: MARK_AS_OVER_ANNOTATED
    reason: Same as the TNF response annotation. Tuba1a is not actively responding
      to glutamate; it is part of the cytoskeleton that is damaged by excitotoxic
      conditions. The response is mediated by HDAC1, not by tubulin.
    supported_by:
    - reference_id: PMID:20037577
      supporting_text: "cultured neurons exposed to glutamate and tumor necrosis factor-alpha"
# ============================================================
# HDA annotation (PMID:17634366) - myelin sheath
# ============================================================
- term:
    id: GO:0043209
    label: myelin sheath
  evidence_type: HDA
  original_reference_id: PMID:17634366
  review:
    summary: PMID:17634366 identified alpha-tubulin in purified myelin membranes by
      proteomics. The study identified >160 proteins in purified myelin membranes.
    action: KEEP_AS_NON_CORE
    reason: Tubulin was detected in myelin proteomics as it is an extremely abundant
      cytoplasmic protein present in oligodendrocyte processes. This is not a primary
      localization for Tuba1a.
    supported_by:
    - reference_id: PMID:17634366
      supporting_text: "By gel-based proteome analysis, we identified >160 proteins\
        \ in purified myelin membranes"
# ============================================================
# IDA annotations - cytoplasmic microtubule
# ============================================================
- term:
    id: GO:0005881
    label: cytoplasmic microtubule
  evidence_type: IDA
  original_reference_id: PMID:19103752
  review:
    summary: PMID:19103752 showed that inhibition of microtubule assembly in osteoblasts
      stimulates BMP-2 expression through Gli2. Alpha-tubulin is a component of cytoplasmic
      microtubules that were disrupted in this study.
    action: ACCEPT
    reason: Correct localization. Tuba1a is a component of cytoplasmic microtubules.
      Consistent with the core function of alpha-tubulin.
- term:
    id: GO:0005881
    label: cytoplasmic microtubule
  evidence_type: IDA
  original_reference_id: PMID:17686994
  review:
    summary: PMID:17686994 studied SYT-SSX2 oncogene remodeling of the cytoskeleton.
      The study detected alpha-tubulin in cytoplasmic microtubules as part of the
      investigation.
    action: ACCEPT
    reason: Correct localization. Alpha-tubulin is a fundamental component of cytoplasmic
      microtubules.
core_functions:
- description: Tuba1a is a structural alpha-tubulin subunit of the microtubule cytoskeleton.
    Alpha/beta-tubulin heterodimers polymerize into cytoplasmic microtubules that
    organize cell architecture and provide tracks for microtubule-dependent processes.
  molecular_function:
    id: GO:0005200
    label: structural constituent of cytoskeleton
  locations:
  - id: GO:0005874
    label: microtubule
  - id: GO:0015630
    label: microtubule cytoskeleton
  - id: GO:0005881
    label: cytoplasmic microtubule
  directly_involved_in:
  - id: GO:0000226
    label: microtubule cytoskeleton organization
  - id: GO:0046785
    label: microtubule polymerization
  supported_by:
  - reference_id: file:mouse/Tuba1a/Tuba1a-uniprot.txt
    supporting_text: Tubulin is the major constituent of microtubules, protein filaments
      consisting of alpha- and beta-tubulin heterodimers.
  - reference_id: PMID:17218254
    supporting_text: The S140G Mutation Reduces GTP Binding and Native Heterodimer
      Formation
  - reference_id: PMID:32184299
    supporting_text: reduced TUBA1A allows for assembly of less microtubules in axons
  - reference_id: file:mouse/Tuba1a/Tuba1a-deep-research-falcon.md
    supporting_text: TUBA1A is a structural microtubule subunit that contributes
      alpha-tubulin to the alpha/beta heterodimer and thereby to the polymerized
      microtubule lattice.
- description: Tuba1a binds GTP at the alpha-tubulin N-site, which stabilizes the
    alpha/beta-tubulin heterodimer needed for microtubule polymerization.
  molecular_function:
    id: GO:0005525
    label: GTP binding
  directly_involved_in:
  - id: GO:0046785
    label: microtubule polymerization
  supported_by:
  - reference_id: PMID:17218254
    supporting_text: The S140G Mutation Reduces GTP Binding and Native Heterodimer
      FormationWe hypothesized that the S140G mutation might affect the ability of
      Tuba1 to bind GTP at the N site
  - reference_id: file:mouse/Tuba1a/Tuba1a-uniprot.txt
    supporting_text: Microtubules grow by the addition of GTP-tubulin dimers to the
      microtubule end, where a stabilizing cap forms.
- description: Tuba1a heterodimerizes with beta-tubulin after chaperone-dependent
    folding, generating the alpha/beta-tubulin heterodimer that is the immediate
    building block of microtubules.
  molecular_function:
    id: GO:0046982
    label: protein heterodimerization activity
  locations:
  - id: GO:0005829
    label: cytosol
  - id: GO:0005874
    label: microtubule
  directly_involved_in:
  - id: GO:0046785
    label: microtubule polymerization
  supported_by:
  - reference_id: PMID:17218254
    supporting_text: Consistent with the data obtained in our GTP labeling experiments,
      we found that the S140G mutation reduced the efficiency of de novo heterodimer
      formation.
  - reference_id: PMID:20603323
    supporting_text: Disease-associated mutations in TUBA1A result in a spectrum of
      defects in the tubulin folding and heterodimer assembly pathway
  - reference_id: file:mouse/Tuba1a/Tuba1a-deep-research-falcon.md
    supporting_text: Microtubules are cytoskeletal polymers built from alpha/beta-tubulin
      heterodimers; TUBA1A is the predominant neuronal alpha-tubulin during brain
      development.
- description: Tuba1a-rich neuronal microtubules support neuronal migration in the
    developing brain. Independent mouse alleles show that altered Tuba1a disrupts
    microtubule geometry, nucleus-centrosome coupling, and radial or saltatory neuronal
    migration.
  molecular_function:
    id: GO:0005200
    label: structural constituent of cytoskeleton
  locations:
  - id: GO:0005881
    label: cytoplasmic microtubule
  directly_involved_in:
  - id: GO:0001764
    label: neuron migration
  supported_by:
  - reference_id: PMID:17218254
    supporting_text: The mutation results in abnormal neuronal migration in vivo;
      perturbations in layers II/III and IV of the visual, auditory, and somatosensory
      cortices; and a fractured pyramidal cell layer in the hippocampus
  - reference_id: PMID:28687665
    supporting_text: Live imaging of Tuba1a-mutant neurons revealed slowed migration
      and increased neuronal branching, which correlated with directionality alterations
      and perturbed nucleus-centrosome (N-C) coupling
  - reference_id: PMID:31386652
    supporting_text: In contrast, loss of Tuba1a is perinatal lethal and leads to
      significant forebrain dysmorphology
  - reference_id: file:mouse/Tuba1a/Tuba1a-deep-research-falcon.md
    supporting_text: A mouse Tuba1a S140G missense mutation results in straighter
      newly polymerized microtubules, slowed neuronal migration, increased branching,
      altered directionality, and perturbed nucleus-centrosome coupling in the rostral
      migratory stream.
- description: Tuba1a is a structural component of mammalian sperm flagellar doublet
    microtubules. This is a precise cellular structural role; the broader sperm-motility
    phenotype is kept non-core because the direct evidence places Tuba1a in the axonemal
    microtubule lattice.
  molecular_function:
    id: GO:0005200
    label: structural constituent of cytoskeleton
  locations:
  - id: GO:0036126
    label: sperm flagellum
  - id: GO:0005879
    label: axonemal microtubule
  supported_by:
  - reference_id: PMID:37865089
    supporting_text: Our in situ cryoET and subtomogram averaging has achieved up
      to 6.0 A reconstructions of native microtubule structures in mouse and human
      sperm samples.
    full_text_unavailable: true
  - reference_id: file:mouse/Tuba1a/Tuba1a-uniprot.txt
    supporting_text: Component of sperm flagellar doublet microtubules.
references:
- id: file:mouse/Tuba1a/Tuba1a-uniprot.txt
  title: UniProt record for mouse Tuba1a (P68369)
  findings:
  - statement: Tuba1a is tubulin alpha-1A, a major constituent of microtubules that
      forms alpha/beta-tubulin heterodimers and is present in sperm flagellar doublet
      microtubules.
  - statement: UniProt records GTP-tubulin dimers, Mg2+ cofactor use, and extensive
      alpha-tubulin post-translational modifications including acetylation, polyglutamylation,
      polyglycylation, and tyrosination/detyrosination.
- id: file:mouse/Tuba1a/Tuba1a-deep-research-falcon.md
  title: Falcon deep research report for mouse Tuba1a
  findings:
  - statement: Falcon verifies the target as mouse Tuba1a/P68369 and summarizes TUBA1A
      as a neuronal alpha-tubulin isotype that heterodimerizes with beta-tubulin and
      incorporates into microtubules.
  - statement: Falcon supports TUBA1A as the predominant developmental neuronal alpha-tubulin,
      with Tuba1a-rich microtubules required for neurite extension, neuronal migration,
      axonal transport, and commissure formation.
  - statement: Falcon summarizes mouse Tuba1a mutant evidence, including Tuba1aND
      dosage-sensitive commissural defects and S140G effects on microtubule straightness
      and neuronal saltatory migration.
- id: GO_REF:0000002
  title: InterPro2GO electronic annotation
  findings: []
- id: GO_REF:0000033
  title: Phylogenetic-based annotations by GO_Central (IBA)
  findings: []
- id: GO_REF:0000044
  title: UniProtKB-SubCell-based electronic annotation
  findings: []
- id: GO_REF:0000096
  title: ISO annotation from human ortholog via UniProt
  findings: []
- id: GO_REF:0000107
  title: ISO annotation from human ortholog
  findings: []
- id: GO_REF:0000119
  title: ISO annotation from human ortholog via GO_Central
  findings: []
- id: GO_REF:0000120
  title: UniProt Annotation Extension electronic annotation
  findings: []
- id: PMID:17218254
  title: Mutations in alpha-tubulin cause abnormal neuronal migration in mice and
    lissencephaly in humans.
  findings:
  - statement: S140G mutation in Tuba1a GTP binding pocket reduces GTP binding 5-fold
      and heterodimer formation
  - statement: Impaired radial migration at E14.5 and E16.5 demonstrated by BrdU labeling
  - statement: Fractured pyramidal cell layer in hippocampus and cortical wave-like
      perturbations
  - statement: Hyperactivity, impaired spatial working memory, and reduced anxiety
  - statement: BAC transgene rescue confirms all phenotypes are due to Tuba1a mutation
  - statement: No cerebellar abnormalities
- id: PMID:17634366
  title: Proteolipid protein is required for transport of sirtuin 2 into CNS myelin.
  findings:
  - statement: Identified alpha-tubulin among >160 proteins in purified myelin membrane
      proteome
- id: PMID:17686994
  title: The synovial sarcoma SYT-SSX2 oncogene remodels the cytoskeleton through
    activation of the ephrin pathway.
  findings:
  - statement: SYT-SSX2 induces microtubule stabilization and accumulation of detyrosinated
      Glu-tubulin
- id: PMID:19056362
  title: Alpha/beta-tubulin are A kinase anchor proteins for type I PKA in neurons.
  findings:
  - statement: Alpha/beta-tubulin forms complex with PKA RI subunit serving as AKAP
  - statement: Complex is produced in cytosol and transported to synapses
  - statement: PKA RI co-localizes with tubulin in neuropils and at cell membrane
- id: PMID:19103752
  title: Inhibition of microtubule assembly in osteoblasts stimulates bone morphogenetic
    protein 2 expression and bone formation through transcription factor Gli2.
  findings:
  - statement: Microtubule inhibition increases Gli2 levels and BMP-2 expression in
      osteoblasts
- id: PMID:19893491
  title: CYLD negatively regulates cell-cycle progression by inactivating HDAC6 and
    increasing the levels of acetylated tubulin.
  findings:
  - statement: CYLD interacts with alpha-tubulin via CAP-Gly domains 1 and 2
  - statement: CYLD inhibits HDAC6-mediated tubulin deacetylation
  - statement: CYLD increases acetylated alpha-tubulin levels
- id: PMID:20037577
  title: HDAC1 nuclear export induced by pathological conditions is essential for
    the onset of axonal damage.
  findings:
  - statement: HDAC1 nuclear export in neurons exposed to glutamate and TNF-alpha
  - statement: HDAC1 interacts with kinesin motor proteins impairing mitochondrial
      transport
  - statement: Axonal damage involves cytoskeletal disruption including tubulin
- id: PMID:20603323
  title: Disease-associated mutations in TUBA1A result in a spectrum of defects in
    the tubulin folding and heterodimer assembly pathway.
  findings:
  - statement: Nine disease-causing TUBA1A mutations examined
  - statement: Defects in chaperone interactions (prefoldin, CCT, TBCB)
  - statement: Reduced heterodimer formation in varying yields
  - statement: Suppressed microtubule growth rate in neurites
- id: PMID:21041996
  title: The role of Tuba1a in adult hippocampal neurogenesis and the formation of
    the dentate gyrus.
  findings:
  - statement: Normal neurogenic potential but ectopic neurogenesis in S140G mutant
  - statement: Disorganized subgranular zone and dispersed granule cell layer
  - statement: Defective migration of neurons and progenitors during development
- id: PMID:21875651
  title: Cytoarchitectural disruption of the superior colliculus and an enlarged acoustic
    startle response in the Tuba1a mutant mouse.
  findings:
  - statement: Superior colliculus thinning with apparent fusion of deep layers
  - statement: Impaired radial migration in SC demonstrated by birthdate labeling
  - statement: Massive neuronal loss attributed to increased apoptotic cell death
  - statement: Exaggerated acoustic startle response
- id: PMID:22101068
  title: Behavioral and neuromorphological characterization of a novel Tuba1 mutant
    mouse.
  findings:
  - statement: D263G mutation (Rgsc1736 allele) causes hyperactivity and cortical
      abnormalities
  - statement: Inattention to novel objects and aberrant home-cage activity patterns
- id: PMID:24244602
  title: "TFIIB co-localizes and interacts with α-tubulin during oocyte meiosis in\
    \ the mouse and depletion of TFIIB causes arrest of subsequent embryo development."
  findings:
  - statement: TFIIB and alpha-tubulin co-localize during meiosis
  - statement: Direct interaction confirmed by BiFC
  - statement: TFIIB associates with spindle microtubules from GVBD to MII
- id: PMID:26658218
  title: "Novel α-tubulin mutation disrupts neural development and tubulin proteostasis."
  findings:
  - statement: Tuba1a ND mutation causes cortical dysgenesis and motor neuron defects
  - statement: Motor neurons fail to innervate limb muscles with synapse defects at
      NMJ
  - statement: Mutant alpha-tubulin depleted from cell lysate and microtubules
  - statement: Tubulin-binding cofactors suppress mutation effects
- id: PMID:27793670
  title: Ciliary smoothened-mediated noncanonical hedgehog signaling promotes tubulin
    acetylation.
  findings:
  - statement: Hh pathway increases microtubule acetylation via Smo
  - statement: Dependent on Smo but not Sufu or Gli
  - statement: Requires primary cilia and intracellular calcium increase
- id: PMID:27976998
  title: Acetylated tubulin is essential for touch sensation in mice.
  findings:
  - statement: Atat1 knockout mice lose mechanosensitivity
  - statement: All cutaneous afferent subtypes have reduced mechanosensitivity
  - statement: Acetylation maintains cellular elasticity required for mechanotransduction
- id: PMID:28687665
  title: "Mutation of the α-tubulin Tuba1a leads to straighter microtubules and perturbs\
    \ neuronal migration."
  findings:
  - statement: S140G mutation causes increased microtubule straightness
  - statement: Slowed neuronal migration with increased branching
  - statement: Perturbed nucleus-centrosome coupling
  - statement: Glial cells dispersed along RMS
  - statement: Tuba1a plays essential non-compensated role in saltatory migration
- id: PMID:31386652
  title: Differential requirements of tubulin genes in mammalian forebrain development.
  findings:
  - statement: Tuba1a null is perinatal lethal with significant forebrain dysmorphology
  - statement: Tubb2a and Tubb2b nulls survive with mild phenotypes
  - statement: Demonstrates non-redundant role of Tuba1a
- id: PMID:32184299
  title: Reduced TUBA1A Tubulin Causes Defects in Trafficking and Impaired Adult Motor
    Behavior.
  findings:
  - statement: Tuba1a ND heterozygotes have reduced microtubule tracks in axons
  - statement: Increased organelle trafficking pausing
  - statement: Adult-onset ataxia
  - statement: Age-related NMJ synapse size reduction without neuronal death
- id: PMID:37865089
  title: De novo protein identification in mammalian sperm using in situ cryoelectron
    tomography and AlphaFold2 docking.
  findings:
  - statement: Tuba1a identified in sperm flagellar doublet microtubules by cryo-ET
      at 7.7 angstrom
  - statement: Structure resolved as component of axonemal doublet microtubules

Gene Description

Existing Annotations Review

Core Functions

Tuba1a is a structural alpha-tubulin subunit of the microtubule cytoskeleton. Alpha/beta-tubulin heterodimers polymerize into cytoplasmic microtubules that organize cell architecture and provide tracks for microtubule-dependent processes.

Tuba1a binds GTP at the alpha-tubulin N-site, which stabilizes the alpha/beta-tubulin heterodimer needed for microtubule polymerization.

Tuba1a heterodimerizes with beta-tubulin after chaperone-dependent folding, generating the alpha/beta-tubulin heterodimer that is the immediate building block of microtubules.

Tuba1a-rich neuronal microtubules support neuronal migration in the developing brain. Independent mouse alleles show that altered Tuba1a disrupts microtubule geometry, nucleus-centrosome coupling, and radial or saltatory neuronal migration.

Tuba1a is a structural component of mammalian sperm flagellar doublet microtubules. This is a precise cellular structural role; the broader sperm-motility phenotype is kept non-core because the direct evidence places Tuba1a in the axonemal microtubule lattice.

References

Deep Research

Falcon

Research report: Mouse Tuba1a (TUBA1A; UniProt P68369) — functional annotation, pathways, localization, and recent advances

0) Target verification (mandatory identity check)

1) Key concepts and definitions (current understanding)

1.1 Microtubules, α/β‑tubulin heterodimers, and isotype biology

1.2 What is special about TUBA1A/Tuba1a?

1.3 “Tubulin code” and PTMs relevant to TUBA1A-containing microtubules

2) Canonical functional annotation (mouse evidence prioritized)

2.1 Primary molecular function

2.2 Subcellular localization

2.3 Biological processes and pathways (process-level “pathways”)

3) Isoform-specific neurodevelopmental roles: key mouse genetic evidence

3.1 Tuba1a loss-of-function model (Tuba1aND, N102D)

3.2 Tuba1a missense model (S140G)

3.3 Mechanism-level expert analysis: why haploinsufficiency may be insufficient to explain many tubulinopathies

4) Recent developments and latest research (prioritizing 2023–2024)

4.1 2023: Synonymous/codon usage can be pathogenic for Tuba1a (mRNA-level mechanism)

4.2 2024: A cerebellar lncRNA (TubAR) promotes TUBB4A–TUBA1A heterodimers to maintain myelination

4.3 2024: Transcriptional regulation—SALL2 directly activates Tuba1a to drive neural differentiation

4.4 2024: New “tubulin code” chemistry connects metabolism to neuronal microtubule dynamics

5) Current applications and real‑world implementations

5.1 Mouse models as functional “assays” for Tuba1a biology

5.2 Experimental tool development (addressing tubulin isotype indistinguishability)

5.3 Clinical genetics and diagnostics (2024 evidence)

6) Relevant statistics and data highlights (from recent studies)

7) Figures (visual evidence)

8) Evidence map (compact summary table)

9) Practical functional annotation summary (for databases)

References (URLs and publication dates available in evidence)

Citations

📄 View Raw YAML