DSCAM (Down Syndrome Cell Adhesion Molecule) is a transmembrane immunoglobulin superfamily member involved in neural development. CRITICAL CAVEAT: Human DSCAM has ONLY 2 isoforms (Long/Short), NOT the 38,016 isoform diversity of Drosophila Dscam1. Vertebrates achieve neuronal self-avoidance through clustered protocadherins instead. The two human isoforms are: (1) Long/CHD2-42 (O60469-1, canonical) and (2) Short/CHD2-52 (O60469-2). UniProt states it is "primarily expressed in brain" and functions as a netrin (NTN1) receptor via Ig-like domains 7-9. Functions in commissural axon guidance. CAUTION: UniProt notes a withdrawn publication about PAK1/FYN/RAC1 interactions. Most annotations should apply to both isoforms given the limited isoform diversity in humans.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
|
GO:0005886
plasma membrane
|
IBA
GO_REF:0000033 |
ACCEPT |
Summary: DSCAM is a type I transmembrane protein that localizes to the plasma membrane. UniProt confirms that the Long isoform (O60469-1) is a single-pass type I membrane protein localized to the cell membrane [PMID:9426258]. The Short isoform lacks the transmembrane domain and is secreted. This annotation is well-supported by the protein's domain architecture and multiple lines of evidence.
Reason: Plasma membrane localization is a core feature of the canonical Long isoform of DSCAM, which contains a transmembrane domain. This is supported by the original cloning paper [PMID:9426258] and UniProt annotations. The IBA annotation from phylogenetic trees is consistent with the conserved transmembrane topology of DSCAM family members across vertebrates.
Supporting Evidence:
PMID:9426258
both containing 10 Ig-C2 domains... with or without the following transmembrane and intracellular domains
|
|
GO:0007156
homophilic cell-cell adhesion
|
IBA
GO_REF:0000033 |
ACCEPT |
Summary: DSCAM mediates homophilic cell-cell adhesion through its extracellular Ig domains. UniProt describes DSCAM as a homodimer that mediates homophilic interactions to promote cell adhesion. This function is documented in experimental studies showing that DSCAM promotes lamina-specific synaptic connections via homophilic interactions [PMID:10925149 per UniProt].
Reason: Homophilic cell adhesion is a core function of DSCAM, well-documented in both human and model organism studies. This is a primary molecular mechanism underlying DSCAM's role in neuronal patterning and self-avoidance. The IBA annotation is consistent with conserved function across vertebrates and experimental evidence from the literature.
Supporting Evidence:
PMID:9426258
DSCAM is involved in neural differentiation and contributes to the central and peripheral nervous system defects in DS
|
|
GO:0007417
central nervous system development
|
IBA
GO_REF:0000033 |
ACCEPT |
Summary: DSCAM is primarily expressed in brain and plays a role in CNS development including commissural axon guidance and neuronal patterning [PMID:9426258, PMID:18585357]. The original cloning paper established its expression in neural tube, cortex, hippocampus, and spinal cord during neuronal differentiation.
Reason: CNS development is a core biological process for DSCAM. The gene was originally identified based on its location in the Down syndrome critical region and its role in nervous system development. Multiple studies confirm DSCAM's function in commissural axon guidance and neuronal connectivity in the developing CNS.
Supporting Evidence:
PMID:9426258
Tissue in situ hybridization analyses of a mouse homolog of the DSCAM gene revealed broad expression within the nervous system at the time of neuronal differentiation in the neural tube, cortex, hippocampus, medulla, spinal cord
|
|
GO:0043025
neuronal cell body
|
IBA
GO_REF:0000033 |
ACCEPT |
Summary: UniProt indicates DSCAM is localized in the soma (neuronal cell body), in addition to axon and growth cone of commissural axons. This subcellular localization is consistent with DSCAM's role in neuronal self-avoidance and maintaining mosaic spacing between cell bodies of amacrine and ganglion cells.
Reason: Neuronal cell body localization is supported by functional studies showing DSCAM mediates heteroneuronal self-avoidance to maintain mosaic spacing between cell bodies. This is a well-established localization pattern for this cell adhesion molecule.
Supporting Evidence:
PMID:18585357
the Down's syndrome Cell Adhesion Molecule (DSCAM), a candidate gene implicated in the mental retardation phenotype of Down's syndrome, is expressed on spinal commissural axons, binds netrin-1, and is necessary for commissural axons to grow toward and across the midline
|
|
GO:0048842
positive regulation of axon extension involved in axon guidance
|
IBA
GO_REF:0000033 |
ACCEPT |
Summary: DSCAM functions as a netrin receptor that positively regulates axon extension during guidance. Studies demonstrate that DSCAM mediates turning responses to netrin-1 and is necessary for commissural axons to grow toward and across the midline [PMID:18585357].
Reason: This is a core function of DSCAM as a netrin receptor. Multiple studies including PMID:18585357 and PMID:19196994 demonstrate DSCAM's role in promoting axon outgrowth and guidance in response to netrin-1. The IBA annotation is well-supported by experimental evidence from vertebrate model systems.
Supporting Evidence:
PMID:18585357
DSCAM and DCC can each mediate a turning response of these neurons to netrin-1
|
|
GO:0007411
axon guidance
|
IBA
GO_REF:0000033 |
ACCEPT |
Summary: DSCAM is a netrin receptor essential for axon guidance, particularly in commissural axon pathfinding. It collaborates with DCC to mediate turning responses to netrin-1 and guides axon projection across the ventral midline to the floor plate [PMID:18585357, PMID:19196994].
Reason: Axon guidance is the primary documented biological function of vertebrate DSCAM. This is supported by multiple high-quality studies demonstrating DSCAM's role as a netrin receptor in commissural axon guidance. This annotation represents a core function of the gene.
Supporting Evidence:
PMID:18585357
DSCAM is a receptor that can mediate turning responses to netrin-1 and support a key role for netrin/DSCAM signaling in commissural axon guidance in vertebrates
PMID:19196994
DSCAM functions as a netrin receptor in commissural axon pathfinding
|
|
GO:0030424
axon
|
IBA
GO_REF:0000033 |
ACCEPT |
Summary: DSCAM is localized to the axon, particularly in commissural neurons. UniProt indicates the Long isoform is localized in "Cell projection, axon" and "Localized in the soma, cell membrane, axon and growth cone of dissociated commissural axons" [PMID:18585357]. DSCAM is expressed on spinal commissural axons and is necessary for axon guidance.
Reason: Axonal localization is a core feature of DSCAM function as a netrin receptor in commissural axon guidance. This is directly supported by experimental evidence showing DSCAM expression on commissural axons [PMID:18585357].
Supporting Evidence:
PMID:18585357
the Down's syndrome Cell Adhesion Molecule (DSCAM)... is expressed on spinal commissural axons
|
|
GO:0070593
dendrite self-avoidance
|
IBA
GO_REF:0000033 |
ACCEPT |
Summary: DSCAM plays a role in neuronal self-avoidance including dendrite self-avoidance. UniProt states DSCAM "Promotes repulsion between specific neuronal processes of either the same cell or the same subtype of cells" and mediates "isoneuronal self-avoidance for creating an orderly dendritic arborization." However, vertebrate DSCAM with only 2 isoforms may have reduced capacity for this function compared to Drosophila Dscam1 which achieves self-avoidance through 38,016 isoforms.
Reason: While vertebrates use clustered protocadherins as the primary self-avoidance mechanism, mammalian DSCAM still contributes to dendrite self-avoidance particularly in retinal neurons. The IBA annotation is consistent with mouse studies showing DSCAM function in dendritic arborization. This represents a conserved function in vertebrates.
Supporting Evidence:
Reactome:R-HSA-376122
DSCAM is selectively expressed in subclasses of cells and suggest that it uses homophilic repulsion to simultaneously promote both self avoidance
|
|
GO:0098632
cell-cell adhesion mediator activity
|
IBA
GO_REF:0000033 |
ACCEPT |
Summary: DSCAM mediates cell-cell adhesion through homophilic interactions. UniProt describes it as a "Cell adhesion molecule" and states DSCAM is a "Homodimer; mediates homophilic interactions to promote cell adhesion." This molecular function is well-supported.
Reason: Cell-cell adhesion mediator activity is a core molecular function of DSCAM. The protein forms homodimers that mediate homophilic intercellular adhesion, promoting lamina-specific synaptic connections and neuronal patterning.
Supporting Evidence:
Reactome:R-HSA-376122
DSCAM and DSCAML1 proteins are involved in homophilic intercellular interactions
|
|
GO:0005576
extracellular region
|
IEA
GO_REF:0000044 |
ACCEPT |
Summary: The Short isoform of DSCAM (O60469-2) lacks the transmembrane domain and is secreted into the extracellular region. UniProt explicitly states "Isoform Short: Secreted." This annotation is appropriate for the Short isoform.
Reason: While the Long isoform is membrane-bound, the Short isoform lacks transmembrane and intracellular domains and is secreted. This IEA annotation correctly captures the extracellular localization of the Short isoform.
Supporting Evidence:
PMID:9426258
both containing 10 Ig-C2 domains... with or without the following transmembrane and intracellular domains
|
|
GO:0005886
plasma membrane
|
IEA
GO_REF:0000120 |
ACCEPT |
Summary: Duplicate of the IBA annotation for plasma membrane already reviewed. DSCAM Long isoform is a single-pass type I membrane protein localized to the cell membrane.
Reason: This is a duplicate annotation with different evidence. The plasma membrane localization is well-supported for the Long isoform. Multiple evidence codes supporting the same term are acceptable.
|
|
GO:0007155
cell adhesion
|
IEA
GO_REF:0000043 |
ACCEPT |
Summary: DSCAM is a cell adhesion molecule. This is a more general term than the homophilic cell-cell adhesion annotation already accepted. The original cloning paper describes DSCAM as a "Down syndrome cell adhesion molecule" [PMID:9426258].
Reason: Cell adhesion is a core function of DSCAM. While GO:0007156 (homophilic cell adhesion) is more specific, this parent term is also accurate. The annotation is consistent with DSCAM's known function.
Supporting Evidence:
PMID:9426258
a novel member of the immunoglobulin (Ig) superfamily that represents a new class of neural cell adhesion molecules
|
|
GO:0007399
nervous system development
|
IEA
GO_REF:0000043 |
ACCEPT |
Summary: DSCAM plays a role in nervous system development. This is a broader term than GO:0007417 (CNS development) already accepted. DSCAM is expressed "within the nervous system at the time of neuronal differentiation" and involved in neural development.
Reason: Nervous system development is a core function of DSCAM. The original characterization paper demonstrated broad expression in the nervous system during neural differentiation. This annotation is consistent with CNS development and axon guidance functions.
Supporting Evidence:
PMID:9426258
broad expression within the nervous system at the time of neuronal differentiation in the neural tube, cortex, hippocampus, medulla, spinal cord and most neural crest-derived tissues
|
|
GO:0030424
axon
|
IEA
GO_REF:0000120 |
ACCEPT |
Summary: Duplicate of the IBA annotation for axon already reviewed. DSCAM is localized to the axon of commissural neurons.
Reason: This is a duplicate annotation with different evidence. Axonal localization is well-supported for DSCAM. Multiple evidence codes for the same term are acceptable.
|
|
GO:0030425
dendrite
|
IEA
GO_REF:0000120 |
ACCEPT |
Summary: UniProt indicates DSCAM Long isoform is localized to "Cell projection, dendrite." This is consistent with DSCAM's role in dendrite self-avoidance and dendritic arborization.
Reason: Dendritic localization is consistent with DSCAM's function in dendrite self-avoidance and creating orderly dendritic arborization. The annotation is well-supported.
|
|
GO:0030426
growth cone
|
IEA
GO_REF:0000120 |
ACCEPT |
Summary: UniProt states DSCAM is "Localized in the soma, cell membrane, axon and growth cone of dissociated commissural axons." Growth cone localization is essential for DSCAM's function in axon guidance and netrin-1 signaling.
Reason: Growth cone localization is critical for DSCAM's function as a netrin receptor mediating axon turning responses. Studies in PMID:22685302 demonstrate DSCAM's role in growth cone collapse in response to netrin-1.
Supporting Evidence:
PMID:22685302
Netrin-1 induces axon growth cone collapse of mouse cerebellum external granule layer (EGL) cells
|
|
GO:0045202
synapse
|
IEA
GO_REF:0000044 |
ACCEPT |
Summary: UniProt indicates DSCAM is localized to "Synapse." DSCAM promotes lamina-specific synaptic connections in the retina and is found at the dendritic spine postsynaptic density [PMID:35914814].
Reason: Synaptic localization is consistent with DSCAM's function in promoting synaptic connectivity via homophilic interactions, particularly in the retina. Recent work identified DSCAM at the postsynaptic density.
Supporting Evidence:
PMID:35914814
some of the proteins encoded by HSA21 were located at the dendritic spine postsynaptic density
|
|
GO:0005515
protein binding
|
IPI
PMID:32296183 A reference map of the human binary protein interactome. |
MARK AS OVER ANNOTATED |
Summary: From HuRI (Human Reference Interactome) high-throughput Y2H screening. The term "protein binding" is uninformative for DSCAM which has well-characterized specific binding partners including NTN1, DCC, UNC5C, DLG2, and PIH1D2.
Reason: While DSCAM does bind proteins, this generic term provides no functional insight. The HuRI study is a systematic proteome-wide screen that detected many interactions but "protein binding" as an MF term is too vague to be useful for DSCAM annotation. More specific terms like "cell-cell adhesion mediator activity" or "netrin receptor binding" are more informative.
Supporting Evidence:
PMID:32296183
Apr 8. A reference map of the human binary protein interactome.
|
|
GO:0005515
protein binding
|
IPI
PMID:32822567 A Human IgSF Cell-Surface Interactome Reveals a Complex Netw... |
MARK AS OVER ANNOTATED |
Summary: From a high-throughput IgSF cell-surface interactome study. This generic term does not capture the specific functional interactions of DSCAM.
Reason: Same rationale as other protein binding annotations. High-throughput screens correctly detect that DSCAM binds proteins, but the GO term is uninformative. More specific molecular function terms are preferred.
Supporting Evidence:
PMID:32822567
A Human IgSF Cell-Surface Interactome Reveals a Complex Network of Protein-Protein Interactions.
|
|
GO:0005515
protein binding
|
IPI
PMID:35914814 Chr21 protein-protein interactions: enrichment in proteins i... |
MARK AS OVER ANNOTATED |
Summary: From chromosome 21 protein-protein interaction study identifying DSCAM interactions with DLGs and DYRK1A at the postsynaptic density [PMID:35914814].
Reason: While this study provides useful functional context (DSCAM-DLG and DSCAM-DYRK1A interactions at postsynapse), the generic "protein binding" term is uninformative. The specific finding about DLG binding would be better captured by a more specific term if available.
Supporting Evidence:
PMID:35914814
an intracellular domain of DSCAM bound either DLGs, which are multimeric scaffolds comprising receptors, ion channels and associated signaling proteins, or DYRK1A
|
|
GO:0007162
negative regulation of cell adhesion
|
IEA
GO_REF:0000107 |
ACCEPT |
Summary: DSCAM mediates repulsion between neuronal processes through homophilic interactions, leading to self-avoidance. UniProt states DSCAM "Promotes repulsion between specific neuronal processes of either the same cell or the same subtype of cells."
Reason: This annotation captures DSCAM's role in neuronal self-avoidance through homophilic repulsion. While DSCAM promotes initial adhesion, the functional outcome is repulsion and negative regulation of further adhesion between sister processes.
|
|
GO:0007411
axon guidance
|
IEA
GO_REF:0000107 |
ACCEPT |
Summary: Duplicate annotation with different evidence code. Axon guidance is a core function of DSCAM already reviewed with IBA evidence.
Reason: Duplicate annotation supporting the core function. Axon guidance via netrin-1 signaling is well-established for DSCAM.
|
|
GO:0038007
netrin-activated signaling pathway
|
IEA
GO_REF:0000107 |
ACCEPT |
Summary: DSCAM functions as a netrin receptor and mediates netrin-activated signaling. Upon binding netrin-1, DSCAM activates downstream signaling including MAPK8 and p38 MAP kinase [PMID:18585357, PMID:19196994].
Reason: This is a core function of DSCAM as a netrin receptor. DSCAM mediates intracellular signaling by stimulating activation of MAPK8 and MAP kinase p38 in response to netrin-1 binding.
Supporting Evidence:
PMID:19196994
DSCAM by itself, in the absence of DCC, is capable of mediating netrin signaling in activating phosphorylation of Fyn and Pak1
|
|
GO:0043025
neuronal cell body
|
IEA
GO_REF:0000107 |
ACCEPT |
Summary: Duplicate annotation with different evidence code. Neuronal cell body localization already reviewed with IBA evidence.
Reason: Duplicate annotation supporting DSCAM localization to soma of neurons.
|
|
GO:0048842
positive regulation of axon extension involved in axon guidance
|
IEA
GO_REF:0000120 |
ACCEPT |
Summary: Duplicate annotation with different evidence code. This core function already reviewed with IBA evidence.
Reason: Duplicate annotation. DSCAM promotes axon extension in response to netrin-1 during commissural axon guidance.
|
|
GO:0070593
dendrite self-avoidance
|
IEA
GO_REF:0000107 |
ACCEPT |
Summary: Duplicate annotation with different evidence code. Dendrite self-avoidance already reviewed with IBA evidence.
Reason: Duplicate annotation. DSCAM contributes to dendrite self-avoidance in vertebrates, particularly in retinal neurons.
|
|
GO:1990782
protein tyrosine kinase binding
|
IEA
GO_REF:0000107 |
ACCEPT |
Summary: DSCAM interacts with tyrosine kinases including FYN and FAK. UniProt states DSCAM "Interacts with PTK2" (FAK) and "Interacts with FYN." DSCAM is phosphorylated at tyrosine residues, and this is enhanced by netrin-1.
Reason: DSCAM binding to protein tyrosine kinases is supported by UniProt annotations describing interactions with PTK2 (FAK) and FYN. Netrin-1 enhances DSCAM tyrosine phosphorylation, suggesting functional relevance of these interactions.
Supporting Evidence:
PMID:22685302
Netrin-1 increases tyrosine phosphorylation of endogenous DSCAM, UNC5C, FAK, Fyn, and PAK1, and promotes complex formation of DSCAM with these signaling molecules
|
|
GO:1990890
netrin receptor binding
|
IEA
GO_REF:0000107 |
ACCEPT |
Summary: GO:1990890 "netrin receptor binding" means binding TO a netrin receptor. DSCAM binds to UNC5C and DCC, both of which are netrin receptors [PMID:22685302]. DSCAM also interacts with DCC via its transmembrane domain, and this interaction is abolished in response to NTN1 (UniProt). The IEA annotation is propagated from mouse Dscam (Q9ERC8) which was experimentally demonstrated to bind UNC5C.
Reason: DSCAM does bind to other netrin receptors (UNC5C and DCC), making "netrin receptor binding" a correct annotation. PMID:22685302 demonstrated that DSCAM interacts with UNC5C and this interaction is stimulated by netrin-1. UniProt confirms DSCAM interacts with DCC. Note that DSCAM itself is ALSO a netrin receptor, but this term captures its ability to bind other netrin receptors, which is functionally important for coordinating attractive and repulsive guidance responses.
Supporting Evidence:
PMID:22685302
DSCAM interacts with UNC5C and this interaction is stimulated by netrin-1 in primary cortical neurons and postnatal cerebellar granule cells
|
|
GO:0007411
axon guidance
|
ISS
GO_REF:0000024 |
ACCEPT |
Summary: Duplicate annotation with ISS evidence. Axon guidance is a core function of DSCAM already reviewed multiple times with IBA and IEA evidence.
Reason: ISS (Inferred from Sequence Similarity) annotation supporting the well-established core function. Multiple evidence codes for the same term are acceptable.
|
|
GO:0030425
dendrite
|
ISS
GO_REF:0000024 |
ACCEPT |
Summary: Duplicate annotation with ISS evidence. Dendrite localization already reviewed with IEA evidence.
Reason: ISS annotation supporting dendritic localization, consistent with DSCAM's role in dendrite self-avoidance.
|
|
GO:0043025
neuronal cell body
|
ISS
GO_REF:0000024 |
ACCEPT |
Summary: Duplicate annotation with ISS evidence. Neuronal cell body localization already reviewed with IBA and IEA evidence.
Reason: ISS annotation supporting soma localization. Multiple evidence codes acceptable.
|
|
GO:1990890
netrin receptor binding
|
IPI
PMID:22685302 Down syndrome cell adhesion molecule (DSCAM) associates with... |
ACCEPT |
Summary: This annotation refers to DSCAM binding to UNC5C, which is a netrin receptor. PMID:22685302 demonstrates that "DSCAM interacts with UNC5C and this interaction is stimulated by netrin-1." However, DSCAM itself IS also a netrin receptor.
Reason: Unlike the IEA annotation for this term, this IPI annotation from PMID:22685302 correctly captures that DSCAM binds to UNC5C (a netrin receptor) in the context of netrin-1 mediated growth cone collapse. DSCAM associates with UNC5C to coordinate netrin-1 repulsion signaling.
Supporting Evidence:
PMID:22685302
DSCAM interacts with UNC5C and this interaction is stimulated by netrin-1 in primary cortical neurons and postnatal cerebellar granule cells
|
|
GO:0007156
homophilic cell-cell adhesion
|
ISS
GO_REF:0000024 |
ACCEPT |
Summary: Duplicate annotation with ISS evidence. Homophilic cell-cell adhesion already reviewed with IBA evidence.
Reason: ISS annotation supporting the core homophilic adhesion function. Multiple evidence codes acceptable.
|
|
GO:0007416
synapse assembly
|
ISS
GO_REF:0000024 |
KEEP AS NON CORE |
Summary: DSCAM promotes lamina-specific synaptic connections via homophilic interactions. UniProt describes DSCAM as an "Adhesion molecule that promotes lamina-specific synaptic connections in the retina."
Reason: While DSCAM contributes to synaptic connectivity through promoting lamina-specific connections, synapse assembly is not the primary function. The core functions are netrin receptor-mediated axon guidance and neuronal self-avoidance. Synapse assembly is a downstream consequence of DSCAM's adhesion properties.
|
|
GO:0010842
retina layer formation
|
ISS
GO_REF:0000024 |
KEEP AS NON CORE |
Summary: DSCAM functions in retinal development, particularly in maintaining mosaic spacing between amacrine and ganglion cells and promoting lamina-specific connections.
Reason: Retina layer formation represents a tissue-specific manifestation of DSCAM's general self-avoidance function. While supported by evidence from mouse studies, this is not a core molecular function but rather a developmental process in a specific tissue context.
|
|
GO:0045202
synapse
|
ISS
GO_REF:0000024 |
ACCEPT |
Summary: Duplicate annotation with ISS evidence. Synapse localization already reviewed with IEA evidence.
Reason: ISS annotation supporting synaptic localization. Consistent with DSCAM's role in promoting synaptic connectivity and its localization at the postsynaptic density [PMID:35914814].
|
|
GO:0060219
camera-type eye photoreceptor cell differentiation
|
ISS
GO_REF:0000024 |
KEEP AS NON CORE |
Summary: This annotation is based on sequence similarity to mouse Dscam. DSCAM is expressed in retinal ganglion cells and amacrine cells, and functions in retinal development.
Reason: Photoreceptor cell differentiation represents a tissue-specific developmental role. This is not a core function of DSCAM but rather reflects its expression and function in retinal development, likely through its self-avoidance mechanisms.
|
|
GO:0005886
plasma membrane
|
ISS
GO_REF:0000024 |
ACCEPT |
Summary: Duplicate annotation with ISS evidence. Plasma membrane localization already reviewed with IBA, IEA, and TAS evidence.
Reason: ISS annotation supporting membrane localization. Multiple evidence codes acceptable.
|
|
GO:0007162
negative regulation of cell adhesion
|
ISS
GO_REF:0000024 |
ACCEPT |
Summary: Duplicate annotation with ISS evidence. Negative regulation of cell adhesion already reviewed with IEA evidence.
Reason: ISS annotation supporting DSCAM's role in neuronal self-avoidance/repulsion.
|
|
GO:0030424
axon
|
ISS
GO_REF:0000024 |
ACCEPT |
Summary: Duplicate annotation with ISS evidence. Axon localization already reviewed with IBA and IEA evidence.
Reason: ISS annotation supporting axonal localization. Multiple evidence codes acceptable.
|
|
GO:0030426
growth cone
|
ISS
GO_REF:0000024 |
ACCEPT |
Summary: Duplicate annotation with ISS evidence. Growth cone localization already reviewed with IEA evidence.
Reason: ISS annotation supporting growth cone localization. Consistent with DSCAM's function in netrin-1-mediated growth cone guidance.
|
|
GO:0070593
dendrite self-avoidance
|
ISS
GO_REF:0000024 |
ACCEPT |
Summary: Duplicate annotation with ISS evidence. Dendrite self-avoidance already reviewed with IBA and IEA evidence.
Reason: ISS annotation supporting dendrite self-avoidance function. Multiple evidence codes acceptable.
|
|
GO:0048842
positive regulation of axon extension involved in axon guidance
|
IDA
PMID:18585357 DSCAM is a netrin receptor that collaborates with DCC in med... |
ACCEPT |
Summary: IDA (Inferred from Direct Assay) annotation from PMID:18585357 which demonstrated that DSCAM is a netrin receptor necessary for commissural axons to grow toward and across the midline. DSCAM mediates turning responses to netrin-1.
Reason: This is a high-quality experimental annotation for a core function. The Cell paper demonstrated that DSCAM and DCC can each mediate turning responses to netrin-1, and DSCAM is necessary for commissural axon guidance.
Supporting Evidence:
PMID:18585357
DSCAM is a receptor that can mediate turning responses to netrin-1 and support a key role for netrin/DSCAM signaling in commissural axon guidance in vertebrates
|
|
GO:0005515
protein binding
|
IPI
PMID:19196994 DSCAM functions as a netrin receptor in commissural axon pat... |
MARK AS OVER ANNOTATED |
Summary: IPI annotation based on interaction with NTN1 (netrin-1) demonstrated in PMID:19196994. While the interaction is real and functionally important, "protein binding" is too generic for this well-characterized receptor-ligand interaction.
Reason: DSCAM binding to netrin-1 is a specific receptor-ligand interaction that should be annotated with a more specific term. The generic "protein binding" term is uninformative when the specific interaction partner (NTN1) is known.
Supporting Evidence:
PMID:19196994
DSCAM is expressed on commissural axons and interacts with Netrin-1, a prototypical guidance cue for commissural axons
|
|
GO:0042327
positive regulation of phosphorylation
|
IDA
PMID:19196994 DSCAM functions as a netrin receptor in commissural axon pat... |
ACCEPT |
Summary: PMID:19196994 demonstrated that DSCAM mediates netrin signaling by activating phosphorylation of Fyn and Pak1. "DSCAM by itself, in the absence of DCC, is capable of mediating netrin signaling in activating phosphorylation of Fyn and Pak1."
Reason: This is a well-supported IDA annotation. The study demonstrated that DSCAM promotes phosphorylation of downstream signaling molecules (Fyn, Pak1) in response to netrin-1, representing a key signaling output of DSCAM receptor activity.
Supporting Evidence:
PMID:19196994
DSCAM by itself, in the absence of DCC, is capable of mediating netrin signaling in activating phosphorylation of Fyn and Pak1
|
|
GO:0005886
plasma membrane
|
TAS
Reactome:R-HSA-376122 |
ACCEPT |
Summary: TAS annotation from Reactome pathway for DSCAM/DSCAML1 homodimerization, which occurs at the plasma membrane.
Reason: Duplicate annotation supporting membrane localization. The Reactome pathway correctly captures DSCAM homodimerization at the cell surface.
|
|
GO:0005886
plasma membrane
|
TAS
PMID:9426258 DSCAM: a novel member of the immunoglobulin superfamily maps... |
ACCEPT |
Summary: TAS annotation from the original DSCAM cloning paper which described the transmembrane domain topology.
Reason: Duplicate annotation from the original characterization paper supporting plasma membrane localization of the Long isoform.
Supporting Evidence:
PMID:9426258
both containing 10 Ig-C2 domains... with or without the following transmembrane and intracellular domains
|
|
GO:0007155
cell adhesion
|
TAS
PMID:9426258 DSCAM: a novel member of the immunoglobulin superfamily maps... |
ACCEPT |
Summary: TAS annotation from the original DSCAM cloning paper which described DSCAM as a novel cell adhesion molecule of the immunoglobulin superfamily.
Reason: Duplicate annotation supporting cell adhesion function from the original characterization paper.
Supporting Evidence:
PMID:9426258
a novel member of the immunoglobulin (Ig) superfamily that represents a new class of neural cell adhesion molecules
|
|
GO:0007399
nervous system development
|
TAS
PMID:9426258 DSCAM: a novel member of the immunoglobulin superfamily maps... |
ACCEPT |
Summary: TAS annotation from the original paper which established DSCAM expression in the nervous system during neural differentiation.
Reason: Duplicate annotation supporting nervous system development function from the original characterization paper.
Supporting Evidence:
PMID:9426258
DSCAM is involved in neural differentiation and contributes to the central and peripheral nervous system defects in DS
|
|
GO:0016020
membrane
|
TAS
PMID:9426258 DSCAM: a novel member of the immunoglobulin superfamily maps... |
ACCEPT |
Summary: TAS annotation from the original paper. GO:0016020 (membrane) is a parent term of GO:0005886 (plasma membrane), which is already well-annotated for DSCAM.
Reason: While this is a broader term than plasma membrane (already annotated), it is accurate for the Long isoform. The original paper described the transmembrane domain structure.
Supporting Evidence:
PMID:9426258
DSCAM: a novel member of the immunoglobulin superfamily maps in a Down syndrome region and is involved in the development of the nervous system.
|
provider: falcon
model: Edison Scientific Literature
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start_time: '2026-03-06T03:10:30.891967'
end_time: '2026-03-06T03:26:26.046928'
duration_seconds: 955.16
template_file: templates/gene_research_go_focused.md
template_variables:
organism: human
gene_id: DSCAM
gene_symbol: DSCAM
uniprot_accession: O60469
protein_description: 'RecName: Full=Cell adhesion molecule DSCAM {ECO:0000305};
AltName: Full=CHD2; AltName: Full=Down syndrome cell adhesion molecule; Flags:
Precursor;'
gene_info: Name=DSCAM;
organism_full: Homo sapiens (Human).
protein_family: Not specified in UniProt
protein_domains: DSCAM/DSCAML_C. (IPR056754); FN3_dom. (IPR003961); FN3_sf. (IPR036116);
Ig-like_dom. (IPR007110); Ig-like_dom_sf. (IPR036179)
provider_config:
timeout: 600
max_retries: 3
parameters:
allowed_domains: []
temperature: 0.1
citation_count: 33
BEFORE YOU BEGIN RESEARCH: You MUST verify you are researching the CORRECT gene/protein. Gene symbols can be ambiguous, especially for less well-characterized genes from non-model organisms.
DO NOT PROCEED WITH RESEARCH ON A DIFFERENT GENE. Instead:
- State clearly: "The gene symbol 'DSCAM' is ambiguous or literature is limited for this specific protein"
- Explain what you found (e.g., "Found extensive literature on a different gene with the same symbol in a different organism")
- Describe the protein based ONLY on the UniProt information provided above
- Suggest that the protein function can be inferred from domain/family information
Please provide a comprehensive research report on the gene DSCAM (gene ID: DSCAM, UniProt: O60469) in human.
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.
Question: You are an expert researcher providing comprehensive, well-cited information.
Provide detailed information focusing on:
1. Key concepts and definitions with current understanding
2. Recent developments and latest research (prioritize 2023-2024 sources)
3. Current applications and real-world implementations
4. Expert opinions and analysis from authoritative sources
5. Relevant statistics and data from recent studies
Format as a comprehensive research report with proper citations. Include URLs and publication dates where available.
Always prioritize recent, authoritative sources and provide specific citations for all major claims.
BEFORE YOU BEGIN RESEARCH: You MUST verify you are researching the CORRECT gene/protein. Gene symbols can be ambiguous, especially for less well-characterized genes from non-model organisms.
DO NOT PROCEED WITH RESEARCH ON A DIFFERENT GENE. Instead:
- State clearly: "The gene symbol 'DSCAM' is ambiguous or literature is limited for this specific protein"
- Explain what you found (e.g., "Found extensive literature on a different gene with the same symbol in a different organism")
- Describe the protein based ONLY on the UniProt information provided above
- Suggest that the protein function can be inferred from domain/family information
Please provide a comprehensive research report on the gene DSCAM (gene ID: DSCAM, UniProt: O60469) in human.
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.
The target gene/protein is DSCAM (Down syndrome cell adhesion molecule) from Homo sapiens, corresponding to UniProt O60469. The literature summarized here consistently describes vertebrate/mammalian DSCAM as an Ig superfamily (IgSF) single-pass transmembrane cell-adhesion receptor with a large extracellular region of 10 Ig domains and 6 fibronectin type III (FNIII) domains, explicitly contrasting it with Drosophila Dscam1, which has extreme alternative-splicing isoform diversity that is absent in vertebrates. This match of organism, name, and domain architecture verifies that the evidence pertains to the intended protein identity (bai2024synapticcelladhesion pages 7-8, xiong2025exploringperspectivesof pages 1-2).
DSCAM is best understood as a cell-surface recognition/adhesion molecule (IgSF CAM) that regulates how developing neurons and circuits are assembled. Its canonical roles are in:
- Neurite patterning (self-avoidance/tiling; spacing and arborization)
- Axon guidance and branching
- Synapse formation and maturation, including trans-cellular interactions at synapses
Vertebrate DSCAM retains homophilic adhesion capacity but is also implicated in heterophilic interactions (e.g., with synaptic and glial partners) that influence circuit wiring and synaptic physiology (bai2024synapticcelladhesion pages 7-8, dewa2024neuronaldscamregulates pages 1-2).
A major unifying concept is dosage sensitivity: both increased and decreased DSCAM function can perturb neural wiring and synaptic development, consistent with DSCAM’s location on human chromosome 21 (HSA21) and involvement in Down syndrome (DS) gene-dosage effects (hergenreder2024theroleof pages 2-3, hergenreder2024theroleof pages 1-2, hergenreder2024theroleof pages 3-5).
Across recent reviews, vertebrate DSCAM is described as:
- Extracellular: 10 Ig + 6 FNIII domains
- Transmembrane: single-pass
- Intracellular: cytoplasmic tail (often discussed as lacking obvious enzymatic motifs but serving as a signaling/scaffold interface)
These features support classification as a signaling-competent adhesion receptor rather than an enzyme or transporter (bai2024synapticcelladhesion pages 7-8, xiong2025exploringperspectivesof pages 1-2).
Experimentally supported localizations emphasize neuronal development sites:
- Axons / growth cones, with local translational regulation in axonal compartments (bai2024synapticcelladhesion pages 7-8, lemieux2021roleofdscam pages 19-21)
- Apical endfeet of differentiating neurons in developing midbrain (key for delamination) (arimura2020dscamregulatesdelamination pages 1-2)
- Synaptic/perisynaptic regions, including a role at tripartite synapses through neuron–glia interaction (dewa2024neuronaldscamregulates pages 1-2, dewa2024neuronaldscamregulates pages 6-7)
DSCAM’s primary function is to regulate cell–cell interactions that instruct neuronal positioning, process routing, and synapse formation, via several mechanistic modules.
A core pathway places DSCAM within netrin-1 guidance responses, acting alongside canonical netrin receptors:
- DSCAM can collaborate with DCC to mediate netrin-1-induced axon outgrowth/attraction.
- DSCAM physically interacts with UNC5C (Unc5c) to mediate netrin-1-dependent growth cone collapse/repulsion, via an intracellular complex involving FYN, FAK, and PAK1.
- Netrin-1 increases colocalization of DSCAM/DCC with axonal cytoskeletal components, and knockdown of DSCAM and/or DCC blocks netrin-1-induced axon branching (lemieux2021roleofdscam pages 3-4, lemieux2021roleofdscam pages 19-21).
A complementary synthesis highlights convergence on microtubule regulation, with TUBB3 described as a point of convergence for DSCAM/DCC/UNC5-associated guidance outputs (xiong2025exploringperspectivesof pages 4-5).
Interpretation: DSCAM acts as a guidance/branching receptor that links extracellular cues (netrin-1) to intracellular cytoskeletal remodeling, thereby controlling axon extension trajectories and collateral branching.
A distinct and well-defined developmental mechanism is adhesion downregulation at the ventricular surface:
- DSCAM locally suppresses the RapGEF2 → Rap1 → N-cadherin cascade at apical endfeet.
- DSCAM physically associates with RapGEF2 and inactivates Rap1; Rap1 activity is required for membrane localization of N-cadherin.
- Functionally, Dscam knockdown increases N-cadherin localization and ventricular attachment area, impairing endfeet detachment; co-knockdown of RapGEF2 or N-cadherin rescues excessive attachment (arimura2020dscamregulatesdelamination pages 1-2).
Interpretation: DSCAM can act as a local “anti-adhesion” regulator enabling neurons to detach (delaminate) and migrate appropriately.
A synaptic mechanism described in DS-focused synthesis is:
- DSCAM’s extracellular domain binds NLGN1 and inhibits the NLGN1–NRXN1β interaction.
- DSCAM deficiency enriches NLGN1 in synaptic membranes and alters excitatory synapse maturation (e.g., more spines during early postnatal windows; altered miniature EPSCs in cortex) (hergenreder2024theroleof pages 3-5).
Interpretation: DSCAM can function as a brake on excitatory synapse maturation, plausibly by competing with or sterically preventing NLGN1–neurexin adhesion.
A 2024 mechanistic advance identified a trans-cellular mechanism linking DSCAM to astrocytic glutamate clearance:
- In developing cerebellum, neuronal DSCAM (Purkinje cells) is required for normal climbing fiber synapse formation/translocation, and mutants show impaired glutamate clearance with delocalization of GLAST away from synaptic clefts.
- GLAST (Bergmann glia glutamate transporter) complexes with DSCAM’s extracellular region, indicating a direct extracellular interaction.
- Pharmacologic reduction of free glutamate using riluzole (activating glutamate transporter-mediated uptake) partly but significantly rescues proximal climbing fiber synaptogenesis defects in Purkinje-cell-selective Dscam deficiency.
- DSCAM is required for motor learning (hOKR adaptation), though not gross coordination (dewa2024neuronaldscamregulates pages 1-2, dewa2024neuronaldscamregulates pages 6-7).
Visual evidence from the same study: immunogold EM and quantitative plots show GLAST positioning relative to postsynaptic densities and its altered distribution in Dscam mutants, and biochemical data show DSCAM–GLAST co-immunoprecipitation (dewa2024neuronaldscamregulates media 7bbc9b3c, dewa2024neuronaldscamregulates media add1b008, dewa2024neuronaldscamregulates media f69e81f1, dewa2024neuronaldscamregulates media 3c0a917e).
Interpretation: DSCAM is not merely “neuronal adhesion”; it can act as a neuron-to-astrocyte organizer of perisynaptic glutamate uptake machinery, linking adhesion biology to synaptic physiology.
DSCAM is part of a fragile X–relevant translational control axis:
- FMRP binds DSCAM mRNA and inhibits translation in Drosophila and mammalian neurons; loss of FMRP increases DSCAM levels in fragile X contexts.
- Netrin-1 can increase DSCAM protein in growing axons, consistent with cue-regulated local translation.
- Reducing DSCAM levels in fragile X models can reduce targeting errors and rescue behavioral responses (bai2024synapticcelladhesion pages 7-8, hergenreder2024theroleof pages 3-5).
Interpretation: DSCAM lies at the intersection of activity/cue-dependent local translation and structural wiring programs relevant to neurodevelopmental disorders.
The most clearly delineated 2024 advance is the discovery that DSCAM’s extracellular domain binds GLAST and is needed for perisynaptic transporter positioning and cerebellar circuit formation, with pharmacologic rescue of a synaptogenesis phenotype (Dewa et al., accepted 19 Dec 2023; published 2024; Nature Communications; https://doi.org/10.1038/s41467-023-44579-z) (dewa2024neuronaldscamregulates pages 1-2, dewa2024neuronaldscamregulates pages 6-7).
A 2024 review frames DSCAM as a dosage-sensitive HSA21 gene that contributes to DS phenotypes and provides DS population statistics and comorbidity frequencies (published online Feb 9, 2024; https://doi.org/10.1515/mr-2023-0056) (hergenreder2024theroleof pages 1-2, hergenreder2024theroleof pages 7-8).
A 2024 PLOS ONE study reports enrichment of CNVs intersecting DSCAM among early-onset bicuspid aortic valve probands with replication in a much larger late-onset cohort (https://doi.org/10.1371/journal.pone.0304514) (carlisle2024raregenomiccopy pages 1-2).
A 2024 review of synaptic CAMs in fragile X highlights DSCAM structure, its regulation by FMRP, axonal localization and netrin responsiveness, and heterophilic partners NLGN1 and GLAST (Frontiers in Cellular Neuroscience, Jul 2024; https://doi.org/10.3389/fncel.2024.1393536) (bai2024synapticcelladhesion pages 7-8).
No DSCAM-targeted therapy is established clinically in the evidence reviewed here, but two mechanism-informed intervention concepts recur:
1. Abl kinase inhibition as a way to counteract DSCAM-driven presynaptic overgrowth phenotypes (suggested in DS/FXS mechanistic synthesis) (hergenreder2024theroleof pages 3-5, hergenreder2024theroleof pages 5-7).
2. Modulating glutamate clearance in circuits where DSCAM organizes glial transporter positioning; in cerebellar Purkinje cell-specific Dscam deficiency, riluzole partially rescues synaptogenesis defects (mouse model) (dewa2024neuronaldscamregulates pages 6-7).
These represent pathway-level applications rather than direct DSCAM pharmacology.
A major real-world implementation relevant to DSCAM variant interpretation is the Simons Searchlight observational registry:
- ClinicalTrials.gov NCT01238250 (recruiting; observational; international, online; estimated enrollment 100,000)
- Enrolls individuals with confirmed pathogenic/likely pathogenic variants (including DSCAM) to collect longitudinal medical/developmental/behavioral outcomes and biospecimens for research and data sharing.
This infrastructure is a practical route for genotype–phenotype aggregation for DSCAM-linked neurodevelopmental disorders (NCT01238250 chunk 1).
The DS-focused review reports:
- DS occurs in about 1 in 800 live births worldwide.
- In neonatal DS: ~40% congenital heart disease; 12% congenital gastrointestinal malformation; 3% imperforate anus; ~3% dense congenital cataracts.
- Neurodegeneration: almost all patients ≥40 show indications of Alzheimer’s disease; ~30% have early-onset Alzheimer’s at age 50; ~50% at age 60.
- Life expectancy is ~60 years, with congenital heart disease a leading cause of death (hergenreder2024theroleof pages 1-2).
These statistics contextualize why HSA21 dosage genes such as DSCAM are clinically consequential.
Expert synthesis emphasizes that DS phenotypes can be polygenic within HSA21, and highlights cooperative effects:
- Co-overexpression of DSCAM and COL6A2 is linked to cardiac malformations in models, supporting a gene–gene interaction framework rather than single-gene sufficiency for some DS phenotypes (hergenreder2024theroleof pages 1-2, hergenreder2024theroleof pages 5-7).
The same 2024 DS-focused review notes Hirschsprung disease affects ~2% of the DS population, and discusses association evidence implicating intronic DSCAM variants in Hirschsprung contexts (hergenreder2024theroleof pages 7-8).
Carlisle et al. (PLOS ONE, Sep 2024; https://doi.org/10.1371/journal.pone.0304514) performed a CNV study:
- Early-onset BAV probands: n = 272; replication late-onset sporadic BAV cohort: n = 5040.
- Potentially pathogenic CNVs were identified in ~9% of EBAV cases.
- A DSCAM-intersecting region test in EBAV reported 4 case CNVs vs 2 control CNVs with OR 67 (P < 0.001) (carlisle2024raregenomiccopy pages 1-2, carlisle2024raregenomiccopy pages 7-8).
These data support DSCAM dosage/structural variation as a plausible contributor to certain congenital valve phenotypes.
| Aspect | Evidence Summary | Key Citations | Recent Source Examples |
|---|---|---|---|
| Protein Type & Domains | Transmembrane immunoglobulin superfamily (IgSF) cell adhesion molecule. Vertebrate DSCAM lacks the extreme splice-isoform diversity of Drosophila Dscam1. Extracellular: 10 Ig domains, 6 FNIII domains; Intracellular: cytoplasmic tail with PDZ-binding motif. | (xiong2025exploringperspectivesof pages 1-2, bai2024synapticcelladhesion pages 7-8, dewa2024neuronaldscamregulates pages 1-2) | Front. Mol. Neurosci. (2025) DOI |
| Subcellular Localization | Localizes to axonal growth cones, dendrites, and synapses. Accumulates at apical endfeet of differentiating neurons (midbrain) and perisynaptic regions (cerebellum). Cytoplasmic domain can be cleaved and imported to the nucleus. | (bai2024synapticcelladhesion pages 7-8, dewa2024neuronaldscamregulates pages 1-2, lemieux2021roleofdscam pages 19-21, arimura2020dscamregulatesdelamination pages 1-2) | Science Advances (2020) DOI; Nat. Commun. (2024) DOI |
| Axon Guidance & Netrin-1 | Functions as a Netrin-1 receptor mediating attraction (with DCC) or repulsion (with UNC5C). Required for commissural axon crossing, turning, and branching; signals converge on TUBB3 microtubule dynamics. | (lemieux2021roleofdscam pages 3-4, xiong2025exploringperspectivesof pages 4-5, lemieux2021roleofdscam pages 19-21) | Int. J. Mol. Sci. (2021) DOI |
| Adhesion & Delamination | Promotes neuronal delamination by suppressing the RapGEF2–Rap1–N-cadherin adhesion cascade. Loss leads to excessive N-cadherin at apical endfeet and migration defects. | (bai2024synapticcelladhesion pages 7-8, arimura2020dscamregulatesdelamination pages 1-2) | Science Advances (2020) DOI |
| Synaptogenesis & Wiring | Regulates synapse maturation and targeting. Extracellularly binds Neuroligin-1 (NLGN1) to inhibit excitatory synapse maturation; interacts transcellularly with astrocytic GLAST to control glutamate clearance and cerebellar circuit wiring. | (hergenreder2024theroleof pages 3-5, dewa2024neuronaldscamregulates pages 1-2) | Nat. Commun. (2024) DOI; Medical Review (2024) DOI |
| Signaling & Regulation | Cytoplasmic domain activates Abl kinase (linked to presynaptic overgrowth) and interacts with scaffolds (MAGI, PSD95). Translationally repressed by FMRP; loss of FMRP phenocopies DSCAM overexpression. | (hergenreder2024theroleof pages 3-5, bai2024synapticcelladhesion pages 7-8, lemieux2021roleofdscam pages 3-4) | Front. Cell. Neurosci. (2024) DOI |
| Down Syndrome (DS) | Located on HSA21 (21q22.3); triplication linked to DS neurodevelopmental and cardiac defects. Overexpression causes excessive GABAergic synapses and, synergistically with COL6A2, drives congenital heart defects. | (hergenreder2024theroleof pages 3-5, hergenreder2024theroleof pages 5-7, hergenreder2024theroleof pages 1-2) | Medical Review (2024) DOI |
| Cardiovascular Disease | Recurrent large rare CNVs intersecting DSCAM (and GATA4) identified in ~9% of early-onset bicuspid aortic valve (BAV) probands. Segregates with BAV in families. | (carlisle2024raregenomiccopy pages 6-7, carlisle2024raregenomiccopy pages 7-8, carlisle2024raregenomiccopy pages 1-2) | PLOS ONE (2024) DOI |
| Autism & ID | Associated with autism spectrum disorder (ASD) and intellectual disability (ID) via dosage sensitivity. Loss leads to premature spine maturation/autism-like behaviors; gain disrupts connectivity. | (xiong2025exploringperspectivesof pages 1-2, bai2024synapticcelladhesion pages 7-8, dewa2024neuronaldscamregulates media 7bbc9b3c) | Front. Cell. Neurosci. (2024) DOI |
| Clinical Implementation | No FDA-approved therapies targeting DSCAM specifically. Monitored in 'Simons Searchlight' registry (NCT01238250) for phenotypic characterization of variants. | (NCT01238250 chunk 1) | ClinicalTrials.gov (2024) NCT01238250 |
Table: This table synthesizes key functional aspects of human DSCAM (UniProt O60469), consolidating evidence on domains, localization, signaling pathways (Netrin-1, RapGEF2, FMRP), and disease associations (Down syndrome, BAV, Autism) from 2020-2024 literature.
Human DSCAM (O60469) encodes a transmembrane IgSF cell-adhesion receptor that functions primarily as a dose-sensitive organizer of neuronal wiring. Mechanistically, it (i) couples extracellular cues such as netrin-1 to cytoskeletal remodeling and axon routing via interactions with DCC/UNC5C and downstream kinase modules; (ii) regulates neuronal delamination/migration by suppressing RapGEF2–Rap1–N-cadherin adhesion at apical endfeet; and (iii) shapes synapse formation and maturation through heterophilic interactions in the synaptic CAM network (e.g., NLGN1, GLAST) and through post-transcriptional control by FMRP. The most recent 2024 work extends DSCAM’s functional footprint to a neuron–astrocyte mechanism that positions glutamate transporters at perisynaptic sites to ensure effective synaptogenesis and learning-related circuit function (dewa2024neuronaldscamregulates pages 1-2, dewa2024neuronaldscamregulates pages 6-7, arimura2020dscamregulatesdelamination pages 1-2, hergenreder2024theroleof pages 3-5, bai2024synapticcelladhesion pages 7-8).
References
(bai2024synapticcelladhesion pages 7-8): Shu-Yuan Bai, De-Yang Zeng, Ming Ouyang, Yan Zeng, Wei Tan, and Lang Xu. Synaptic cell adhesion molecules contribute to the pathogenesis and progression of fragile x syndrome. Frontiers in Cellular Neuroscience, Jul 2024. URL: https://doi.org/10.3389/fncel.2024.1393536, doi:10.3389/fncel.2024.1393536. This article has 3 citations.
(xiong2025exploringperspectivesof pages 1-2): Yinyi Xiong, Li Li, and Xiaorong Zhang. Exploring perspectives of dscam for cognitive deficits: a review of multifunction for regulating neural wiring in homeostasis. Frontiers in Molecular Neuroscience, May 2025. URL: https://doi.org/10.3389/fnmol.2025.1575348, doi:10.3389/fnmol.2025.1575348. This article has 2 citations.
(dewa2024neuronaldscamregulates pages 1-2): Ken-ichi Dewa, N. Arimura, W. Kakegawa, Masayuki Itoh, T. Adachi, Satoshi Miyashita, Yukiko U. Inoue, Kento Hizawa, Kei Hori, Natsumi Honjoya, Haruya Yagishita, S. Taya, T. Miyazaki, Chika Usui, Shoji Tatsumoto, Akiko Tsuzuki, Hirotomo Uetake, Kazuhisa Sakai, Kazuhiro Yamakawa, Takuya Sasaki, Jun Nagai, Yoshiya Kawaguchi, Masaki Sone, Takayoshi Inoue, Yasuhiro Go, N. Ichinohe, Kozo Kaibuchi, Masahiko Watanabe, Schuichi Koizumi, M. Yuzaki, and Mikio Hoshino. Neuronal dscam regulates the peri-synaptic localization of glast in bergmann glia for functional synapse formation. Nature Communications, Feb 2024. URL: https://doi.org/10.1038/s41467-023-44579-z, doi:10.1038/s41467-023-44579-z. This article has 16 citations and is from a highest quality peer-reviewed journal.
(hergenreder2024theroleof pages 2-3): Ty Hergenreder, Tao Yang, and Bing Ye. The role of down syndrome cell adhesion molecule in down syndrome. Medical Review, 4:31-41, Feb 2024. URL: https://doi.org/10.1515/mr-2023-0056, doi:10.1515/mr-2023-0056. This article has 5 citations.
(hergenreder2024theroleof pages 1-2): Ty Hergenreder, Tao Yang, and Bing Ye. The role of down syndrome cell adhesion molecule in down syndrome. Medical Review, 4:31-41, Feb 2024. URL: https://doi.org/10.1515/mr-2023-0056, doi:10.1515/mr-2023-0056. This article has 5 citations.
(hergenreder2024theroleof pages 3-5): Ty Hergenreder, Tao Yang, and Bing Ye. The role of down syndrome cell adhesion molecule in down syndrome. Medical Review, 4:31-41, Feb 2024. URL: https://doi.org/10.1515/mr-2023-0056, doi:10.1515/mr-2023-0056. This article has 5 citations.
(lemieux2021roleofdscam pages 19-21): Maxime Lemieux, Louise Thiry, Olivier D. Laflamme, and Frédéric Bretzner. Role of dscam in the development of neural control of movement and locomotion. International Journal of Molecular Sciences, 22:8511, Aug 2021. URL: https://doi.org/10.3390/ijms22168511, doi:10.3390/ijms22168511. This article has 12 citations.
(arimura2020dscamregulatesdelamination pages 1-2): Nariko Arimura, Mako Okada, Shinichiro Taya, Ken-ichi Dewa, Akiko Tsuzuki, Hirotomo Uetake, Satoshi Miyashita, Koichi Hashizume, Kazumi Shimaoka, Saki Egusa, Tomoki Nishioka, Yuchio Yanagawa, Kazuhiro Yamakawa, Yukiko U. Inoue, Takayoshi Inoue, Kozo Kaibuchi, and Mikio Hoshino. Dscam regulates delamination of neurons in the developing midbrain. Science Advances, Sep 2020. URL: https://doi.org/10.1126/sciadv.aba1693, doi:10.1126/sciadv.aba1693. This article has 32 citations and is from a highest quality peer-reviewed journal.
(dewa2024neuronaldscamregulates pages 6-7): Ken-ichi Dewa, N. Arimura, W. Kakegawa, Masayuki Itoh, T. Adachi, Satoshi Miyashita, Yukiko U. Inoue, Kento Hizawa, Kei Hori, Natsumi Honjoya, Haruya Yagishita, S. Taya, T. Miyazaki, Chika Usui, Shoji Tatsumoto, Akiko Tsuzuki, Hirotomo Uetake, Kazuhisa Sakai, Kazuhiro Yamakawa, Takuya Sasaki, Jun Nagai, Yoshiya Kawaguchi, Masaki Sone, Takayoshi Inoue, Yasuhiro Go, N. Ichinohe, Kozo Kaibuchi, Masahiko Watanabe, Schuichi Koizumi, M. Yuzaki, and Mikio Hoshino. Neuronal dscam regulates the peri-synaptic localization of glast in bergmann glia for functional synapse formation. Nature Communications, Feb 2024. URL: https://doi.org/10.1038/s41467-023-44579-z, doi:10.1038/s41467-023-44579-z. This article has 16 citations and is from a highest quality peer-reviewed journal.
(lemieux2021roleofdscam pages 3-4): Maxime Lemieux, Louise Thiry, Olivier D. Laflamme, and Frédéric Bretzner. Role of dscam in the development of neural control of movement and locomotion. International Journal of Molecular Sciences, 22:8511, Aug 2021. URL: https://doi.org/10.3390/ijms22168511, doi:10.3390/ijms22168511. This article has 12 citations.
(xiong2025exploringperspectivesof pages 4-5): Yinyi Xiong, Li Li, and Xiaorong Zhang. Exploring perspectives of dscam for cognitive deficits: a review of multifunction for regulating neural wiring in homeostasis. Frontiers in Molecular Neuroscience, May 2025. URL: https://doi.org/10.3389/fnmol.2025.1575348, doi:10.3389/fnmol.2025.1575348. This article has 2 citations.
(dewa2024neuronaldscamregulates media 7bbc9b3c): Ken-ichi Dewa, N. Arimura, W. Kakegawa, Masayuki Itoh, T. Adachi, Satoshi Miyashita, Yukiko U. Inoue, Kento Hizawa, Kei Hori, Natsumi Honjoya, Haruya Yagishita, S. Taya, T. Miyazaki, Chika Usui, Shoji Tatsumoto, Akiko Tsuzuki, Hirotomo Uetake, Kazuhisa Sakai, Kazuhiro Yamakawa, Takuya Sasaki, Jun Nagai, Yoshiya Kawaguchi, Masaki Sone, Takayoshi Inoue, Yasuhiro Go, N. Ichinohe, Kozo Kaibuchi, Masahiko Watanabe, Schuichi Koizumi, M. Yuzaki, and Mikio Hoshino. Neuronal dscam regulates the peri-synaptic localization of glast in bergmann glia for functional synapse formation. Nature Communications, Feb 2024. URL: https://doi.org/10.1038/s41467-023-44579-z, doi:10.1038/s41467-023-44579-z. This article has 16 citations and is from a highest quality peer-reviewed journal.
(dewa2024neuronaldscamregulates media add1b008): Ken-ichi Dewa, N. Arimura, W. Kakegawa, Masayuki Itoh, T. Adachi, Satoshi Miyashita, Yukiko U. Inoue, Kento Hizawa, Kei Hori, Natsumi Honjoya, Haruya Yagishita, S. Taya, T. Miyazaki, Chika Usui, Shoji Tatsumoto, Akiko Tsuzuki, Hirotomo Uetake, Kazuhisa Sakai, Kazuhiro Yamakawa, Takuya Sasaki, Jun Nagai, Yoshiya Kawaguchi, Masaki Sone, Takayoshi Inoue, Yasuhiro Go, N. Ichinohe, Kozo Kaibuchi, Masahiko Watanabe, Schuichi Koizumi, M. Yuzaki, and Mikio Hoshino. Neuronal dscam regulates the peri-synaptic localization of glast in bergmann glia for functional synapse formation. Nature Communications, Feb 2024. URL: https://doi.org/10.1038/s41467-023-44579-z, doi:10.1038/s41467-023-44579-z. This article has 16 citations and is from a highest quality peer-reviewed journal.
(dewa2024neuronaldscamregulates media f69e81f1): Ken-ichi Dewa, N. Arimura, W. Kakegawa, Masayuki Itoh, T. Adachi, Satoshi Miyashita, Yukiko U. Inoue, Kento Hizawa, Kei Hori, Natsumi Honjoya, Haruya Yagishita, S. Taya, T. Miyazaki, Chika Usui, Shoji Tatsumoto, Akiko Tsuzuki, Hirotomo Uetake, Kazuhisa Sakai, Kazuhiro Yamakawa, Takuya Sasaki, Jun Nagai, Yoshiya Kawaguchi, Masaki Sone, Takayoshi Inoue, Yasuhiro Go, N. Ichinohe, Kozo Kaibuchi, Masahiko Watanabe, Schuichi Koizumi, M. Yuzaki, and Mikio Hoshino. Neuronal dscam regulates the peri-synaptic localization of glast in bergmann glia for functional synapse formation. Nature Communications, Feb 2024. URL: https://doi.org/10.1038/s41467-023-44579-z, doi:10.1038/s41467-023-44579-z. This article has 16 citations and is from a highest quality peer-reviewed journal.
(dewa2024neuronaldscamregulates media 3c0a917e): Ken-ichi Dewa, N. Arimura, W. Kakegawa, Masayuki Itoh, T. Adachi, Satoshi Miyashita, Yukiko U. Inoue, Kento Hizawa, Kei Hori, Natsumi Honjoya, Haruya Yagishita, S. Taya, T. Miyazaki, Chika Usui, Shoji Tatsumoto, Akiko Tsuzuki, Hirotomo Uetake, Kazuhisa Sakai, Kazuhiro Yamakawa, Takuya Sasaki, Jun Nagai, Yoshiya Kawaguchi, Masaki Sone, Takayoshi Inoue, Yasuhiro Go, N. Ichinohe, Kozo Kaibuchi, Masahiko Watanabe, Schuichi Koizumi, M. Yuzaki, and Mikio Hoshino. Neuronal dscam regulates the peri-synaptic localization of glast in bergmann glia for functional synapse formation. Nature Communications, Feb 2024. URL: https://doi.org/10.1038/s41467-023-44579-z, doi:10.1038/s41467-023-44579-z. This article has 16 citations and is from a highest quality peer-reviewed journal.
(hergenreder2024theroleof pages 7-8): Ty Hergenreder, Tao Yang, and Bing Ye. The role of down syndrome cell adhesion molecule in down syndrome. Medical Review, 4:31-41, Feb 2024. URL: https://doi.org/10.1515/mr-2023-0056, doi:10.1515/mr-2023-0056. This article has 5 citations.
(carlisle2024raregenomiccopy pages 1-2): Steven G. Carlisle, Hasan Albasha, Hector Michelena, Anna Sabate-Rotes, Lisa Bianco, Julie De Backer, Laura Muiño Mosquera, Anji T. Yetman, Malenka M Bissell, Maria Grazia Andreassi, Ilenia Foffa, Dawn S. Hui, Anthony Caffarelli, Yuli Y. Kim, Dong-Chuan Guo, Rodolfo Citro, Margot De Marco, Justin T. Tretter, Kim L. McBride, Dianna M. Milewicz, Simon C. Body, and Siddharth K. Prakash. Rare genomic copy number variants implicate new candidate genes for bicuspid aortic valve. PLOS ONE, Sep 2024. URL: https://doi.org/10.1371/journal.pone.0304514, doi:10.1371/journal.pone.0304514. This article has 7 citations and is from a peer-reviewed journal.
(hergenreder2024theroleof pages 5-7): Ty Hergenreder, Tao Yang, and Bing Ye. The role of down syndrome cell adhesion molecule in down syndrome. Medical Review, 4:31-41, Feb 2024. URL: https://doi.org/10.1515/mr-2023-0056, doi:10.1515/mr-2023-0056. This article has 5 citations.
(NCT01238250 chunk 1): Online Study of People Who Have Genetic Changes and Features of Autism: Simons Searchlight. Simons Searchlight. 2010. ClinicalTrials.gov Identifier: NCT01238250
(carlisle2024raregenomiccopy pages 7-8): Steven G. Carlisle, Hasan Albasha, Hector Michelena, Anna Sabate-Rotes, Lisa Bianco, Julie De Backer, Laura Muiño Mosquera, Anji T. Yetman, Malenka M Bissell, Maria Grazia Andreassi, Ilenia Foffa, Dawn S. Hui, Anthony Caffarelli, Yuli Y. Kim, Dong-Chuan Guo, Rodolfo Citro, Margot De Marco, Justin T. Tretter, Kim L. McBride, Dianna M. Milewicz, Simon C. Body, and Siddharth K. Prakash. Rare genomic copy number variants implicate new candidate genes for bicuspid aortic valve. PLOS ONE, Sep 2024. URL: https://doi.org/10.1371/journal.pone.0304514, doi:10.1371/journal.pone.0304514. This article has 7 citations and is from a peer-reviewed journal.
(carlisle2024raregenomiccopy pages 6-7): Steven G. Carlisle, Hasan Albasha, Hector Michelena, Anna Sabate-Rotes, Lisa Bianco, Julie De Backer, Laura Muiño Mosquera, Anji T. Yetman, Malenka M Bissell, Maria Grazia Andreassi, Ilenia Foffa, Dawn S. Hui, Anthony Caffarelli, Yuli Y. Kim, Dong-Chuan Guo, Rodolfo Citro, Margot De Marco, Justin T. Tretter, Kim L. McBride, Dianna M. Milewicz, Simon C. Body, and Siddharth K. Prakash. Rare genomic copy number variants implicate new candidate genes for bicuspid aortic valve. PLOS ONE, Sep 2024. URL: https://doi.org/10.1371/journal.pone.0304514, doi:10.1371/journal.pone.0304514. This article has 7 citations and is from a peer-reviewed journal.
Human DSCAM has ONLY 2 isoforms - NOT the extreme diversity of Drosophila Dscam1!
UniProt lists only 2 isoforms:
| Isoform | UniProt ID | Synonym | Feature |
|---|---|---|---|
| Long | O60469-1 | CHD2-42 | Displayed/canonical |
| Short | O60469-2 | CHD2-52 | Alternative splicing |
Vertebrates use clustered protocadherins (PCDH) instead:
- 50+ protocadherin genes
- Stochastic expression creates unique cell identity
- Provides self-avoidance mechanism analogous to Dscam1
Per UniProt:
- "Primarily expressed in brain"
- "Ig-like C2-type domains 7 to 9 are sufficient for interaction with NTN1"
- Functions as netrin receptor
- Involved in commissural axon guidance
Important caveat in UniProt:
"Has been reported to enhance netrin-induced phosphorylation of PAK1 and FYN; and the interaction between DSCAM, PAK1 and RAC1 has been described. This article has been withdrawn by the authors."
id: O60469
gene_symbol: DSCAM
product_type: PROTEIN
status: DRAFT
taxon:
id: NCBITaxon:9606
label: Homo sapiens
description: 'DSCAM (Down Syndrome Cell Adhesion Molecule) is a transmembrane immunoglobulin superfamily
member involved in neural development. CRITICAL CAVEAT: Human DSCAM has ONLY 2 isoforms (Long/Short),
NOT the 38,016 isoform diversity of Drosophila Dscam1. Vertebrates achieve neuronal self-avoidance through
clustered protocadherins instead. The two human isoforms are: (1) Long/CHD2-42 (O60469-1, canonical)
and (2) Short/CHD2-52 (O60469-2). UniProt states it is "primarily expressed in brain" and functions
as a netrin (NTN1) receptor via Ig-like domains 7-9. Functions in commissural axon guidance. CAUTION:
UniProt notes a withdrawn publication about PAK1/FYN/RAC1 interactions. Most annotations should apply
to both isoforms given the limited isoform diversity in humans.'
existing_annotations:
- term:
id: GO:0005886
label: plasma membrane
evidence_type: IBA
original_reference_id: GO_REF:0000033
review:
summary: DSCAM is a type I transmembrane protein that localizes to the plasma membrane. UniProt confirms
that the Long isoform (O60469-1) is a single-pass type I membrane protein localized to the cell
membrane [PMID:9426258]. The Short isoform lacks the transmembrane domain and is secreted. This
annotation is well-supported by the protein's domain architecture and multiple lines of evidence.
action: ACCEPT
reason: Plasma membrane localization is a core feature of the canonical Long isoform of DSCAM, which
contains a transmembrane domain. This is supported by the original cloning paper [PMID:9426258]
and UniProt annotations. The IBA annotation from phylogenetic trees is consistent with the conserved
transmembrane topology of DSCAM family members across vertebrates.
supported_by:
- reference_id: PMID:9426258
supporting_text: both containing 10 Ig-C2 domains... with or without the following transmembrane
and intracellular domains
- term:
id: GO:0007156
label: homophilic cell-cell adhesion
evidence_type: IBA
original_reference_id: GO_REF:0000033
review:
summary: DSCAM mediates homophilic cell-cell adhesion through its extracellular Ig domains. UniProt
describes DSCAM as a homodimer that mediates homophilic interactions to promote cell adhesion. This
function is documented in experimental studies showing that DSCAM promotes lamina-specific synaptic
connections via homophilic interactions [PMID:10925149 per UniProt].
action: ACCEPT
reason: Homophilic cell adhesion is a core function of DSCAM, well-documented in both human and model
organism studies. This is a primary molecular mechanism underlying DSCAM's role in neuronal patterning
and self-avoidance. The IBA annotation is consistent with conserved function across vertebrates
and experimental evidence from the literature.
supported_by:
- reference_id: PMID:9426258
supporting_text: DSCAM is involved in neural differentiation and contributes to the central and
peripheral nervous system defects in DS
- term:
id: GO:0007417
label: central nervous system development
evidence_type: IBA
original_reference_id: GO_REF:0000033
review:
summary: DSCAM is primarily expressed in brain and plays a role in CNS development including commissural
axon guidance and neuronal patterning [PMID:9426258, PMID:18585357]. The original cloning paper
established its expression in neural tube, cortex, hippocampus, and spinal cord during neuronal
differentiation.
action: ACCEPT
reason: CNS development is a core biological process for DSCAM. The gene was originally identified
based on its location in the Down syndrome critical region and its role in nervous system development.
Multiple studies confirm DSCAM's function in commissural axon guidance and neuronal connectivity
in the developing CNS.
supported_by:
- reference_id: PMID:9426258
supporting_text: Tissue in situ hybridization analyses of a mouse homolog of the DSCAM gene revealed
broad expression within the nervous system at the time of neuronal differentiation in the neural
tube, cortex, hippocampus, medulla, spinal cord
- term:
id: GO:0043025
label: neuronal cell body
evidence_type: IBA
original_reference_id: GO_REF:0000033
review:
summary: UniProt indicates DSCAM is localized in the soma (neuronal cell body), in addition to axon
and growth cone of commissural axons. This subcellular localization is consistent with DSCAM's role
in neuronal self-avoidance and maintaining mosaic spacing between cell bodies of amacrine and ganglion
cells.
action: ACCEPT
reason: Neuronal cell body localization is supported by functional studies showing DSCAM mediates
heteroneuronal self-avoidance to maintain mosaic spacing between cell bodies. This is a well-established
localization pattern for this cell adhesion molecule.
supported_by:
- reference_id: PMID:18585357
supporting_text: the Down's syndrome Cell Adhesion Molecule (DSCAM), a candidate gene implicated
in the mental retardation phenotype of Down's syndrome, is expressed on spinal commissural axons,
binds netrin-1, and is necessary for commissural axons to grow toward and across the midline
- term:
id: GO:0048842
label: positive regulation of axon extension involved in axon guidance
evidence_type: IBA
original_reference_id: GO_REF:0000033
review:
summary: DSCAM functions as a netrin receptor that positively regulates axon extension during guidance.
Studies demonstrate that DSCAM mediates turning responses to netrin-1 and is necessary for commissural
axons to grow toward and across the midline [PMID:18585357].
action: ACCEPT
reason: This is a core function of DSCAM as a netrin receptor. Multiple studies including PMID:18585357
and PMID:19196994 demonstrate DSCAM's role in promoting axon outgrowth and guidance in response
to netrin-1. The IBA annotation is well-supported by experimental evidence from vertebrate model
systems.
supported_by:
- reference_id: PMID:18585357
supporting_text: DSCAM and DCC can each mediate a turning response of these neurons to netrin-1
- term:
id: GO:0007411
label: axon guidance
evidence_type: IBA
original_reference_id: GO_REF:0000033
review:
summary: DSCAM is a netrin receptor essential for axon guidance, particularly in commissural axon
pathfinding. It collaborates with DCC to mediate turning responses to netrin-1 and guides axon projection
across the ventral midline to the floor plate [PMID:18585357, PMID:19196994].
action: ACCEPT
reason: Axon guidance is the primary documented biological function of vertebrate DSCAM. This is supported
by multiple high-quality studies demonstrating DSCAM's role as a netrin receptor in commissural
axon guidance. This annotation represents a core function of the gene.
supported_by:
- reference_id: PMID:18585357
supporting_text: DSCAM is a receptor that can mediate turning responses to netrin-1 and support
a key role for netrin/DSCAM signaling in commissural axon guidance in vertebrates
- reference_id: PMID:19196994
supporting_text: DSCAM functions as a netrin receptor in commissural axon pathfinding
- term:
id: GO:0030424
label: axon
evidence_type: IBA
original_reference_id: GO_REF:0000033
review:
summary: DSCAM is localized to the axon, particularly in commissural neurons. UniProt indicates the
Long isoform is localized in "Cell projection, axon" and "Localized in the soma, cell membrane,
axon and growth cone of dissociated commissural axons" [PMID:18585357]. DSCAM is expressed on spinal
commissural axons and is necessary for axon guidance.
action: ACCEPT
reason: Axonal localization is a core feature of DSCAM function as a netrin receptor in commissural
axon guidance. This is directly supported by experimental evidence showing DSCAM expression on commissural
axons [PMID:18585357].
supported_by:
- reference_id: PMID:18585357
supporting_text: the Down's syndrome Cell Adhesion Molecule (DSCAM)... is expressed on spinal commissural
axons
- term:
id: GO:0070593
label: dendrite self-avoidance
evidence_type: IBA
original_reference_id: GO_REF:0000033
review:
summary: DSCAM plays a role in neuronal self-avoidance including dendrite self-avoidance. UniProt
states DSCAM "Promotes repulsion between specific neuronal processes of either the same cell or
the same subtype of cells" and mediates "isoneuronal self-avoidance for creating an orderly dendritic
arborization." However, vertebrate DSCAM with only 2 isoforms may have reduced capacity for this
function compared to Drosophila Dscam1 which achieves self-avoidance through 38,016 isoforms.
action: ACCEPT
reason: While vertebrates use clustered protocadherins as the primary self-avoidance mechanism, mammalian
DSCAM still contributes to dendrite self-avoidance particularly in retinal neurons. The IBA annotation
is consistent with mouse studies showing DSCAM function in dendritic arborization. This represents
a conserved function in vertebrates.
supported_by:
- reference_id: Reactome:R-HSA-376122
supporting_text: DSCAM is selectively expressed in subclasses of cells and suggest that it uses
homophilic repulsion to simultaneously promote both self avoidance
- term:
id: GO:0098632
label: cell-cell adhesion mediator activity
evidence_type: IBA
original_reference_id: GO_REF:0000033
review:
summary: DSCAM mediates cell-cell adhesion through homophilic interactions. UniProt describes it as
a "Cell adhesion molecule" and states DSCAM is a "Homodimer; mediates homophilic interactions to
promote cell adhesion." This molecular function is well-supported.
action: ACCEPT
reason: Cell-cell adhesion mediator activity is a core molecular function of DSCAM. The protein forms
homodimers that mediate homophilic intercellular adhesion, promoting lamina-specific synaptic connections
and neuronal patterning.
supported_by:
- reference_id: Reactome:R-HSA-376122
supporting_text: DSCAM and DSCAML1 proteins are involved in homophilic intercellular interactions
- term:
id: GO:0005576
label: extracellular region
evidence_type: IEA
original_reference_id: GO_REF:0000044
review:
summary: 'The Short isoform of DSCAM (O60469-2) lacks the transmembrane domain and is secreted into
the extracellular region. UniProt explicitly states "Isoform Short: Secreted." This annotation is
appropriate for the Short isoform.'
action: ACCEPT
reason: While the Long isoform is membrane-bound, the Short isoform lacks transmembrane and intracellular
domains and is secreted. This IEA annotation correctly captures the extracellular localization of
the Short isoform.
supported_by:
- reference_id: PMID:9426258
supporting_text: both containing 10 Ig-C2 domains... with or without the following transmembrane
and intracellular domains
- term:
id: GO:0005886
label: plasma membrane
evidence_type: IEA
original_reference_id: GO_REF:0000120
review:
summary: Duplicate of the IBA annotation for plasma membrane already reviewed. DSCAM Long isoform
is a single-pass type I membrane protein localized to the cell membrane.
action: ACCEPT
reason: This is a duplicate annotation with different evidence. The plasma membrane localization is
well-supported for the Long isoform. Multiple evidence codes supporting the same term are acceptable.
- term:
id: GO:0007155
label: cell adhesion
evidence_type: IEA
original_reference_id: GO_REF:0000043
review:
summary: DSCAM is a cell adhesion molecule. This is a more general term than the homophilic cell-cell
adhesion annotation already accepted. The original cloning paper describes DSCAM as a "Down syndrome
cell adhesion molecule" [PMID:9426258].
action: ACCEPT
reason: Cell adhesion is a core function of DSCAM. While GO:0007156 (homophilic cell adhesion) is
more specific, this parent term is also accurate. The annotation is consistent with DSCAM's known
function.
supported_by:
- reference_id: PMID:9426258
supporting_text: a novel member of the immunoglobulin (Ig) superfamily that represents a new class
of neural cell adhesion molecules
- term:
id: GO:0007399
label: nervous system development
evidence_type: IEA
original_reference_id: GO_REF:0000043
review:
summary: DSCAM plays a role in nervous system development. This is a broader term than GO:0007417
(CNS development) already accepted. DSCAM is expressed "within the nervous system at the time of
neuronal differentiation" and involved in neural development.
action: ACCEPT
reason: Nervous system development is a core function of DSCAM. The original characterization paper
demonstrated broad expression in the nervous system during neural differentiation. This annotation
is consistent with CNS development and axon guidance functions.
supported_by:
- reference_id: PMID:9426258
supporting_text: broad expression within the nervous system at the time of neuronal differentiation
in the neural tube, cortex, hippocampus, medulla, spinal cord and most neural crest-derived tissues
- term:
id: GO:0030424
label: axon
evidence_type: IEA
original_reference_id: GO_REF:0000120
review:
summary: Duplicate of the IBA annotation for axon already reviewed. DSCAM is localized to the axon
of commissural neurons.
action: ACCEPT
reason: This is a duplicate annotation with different evidence. Axonal localization is well-supported
for DSCAM. Multiple evidence codes for the same term are acceptable.
- term:
id: GO:0030425
label: dendrite
evidence_type: IEA
original_reference_id: GO_REF:0000120
review:
summary: UniProt indicates DSCAM Long isoform is localized to "Cell projection, dendrite." This is
consistent with DSCAM's role in dendrite self-avoidance and dendritic arborization.
action: ACCEPT
reason: Dendritic localization is consistent with DSCAM's function in dendrite self-avoidance and
creating orderly dendritic arborization. The annotation is well-supported.
- term:
id: GO:0030426
label: growth cone
evidence_type: IEA
original_reference_id: GO_REF:0000120
review:
summary: UniProt states DSCAM is "Localized in the soma, cell membrane, axon and growth cone of dissociated
commissural axons." Growth cone localization is essential for DSCAM's function in axon guidance
and netrin-1 signaling.
action: ACCEPT
reason: Growth cone localization is critical for DSCAM's function as a netrin receptor mediating axon
turning responses. Studies in PMID:22685302 demonstrate DSCAM's role in growth cone collapse in
response to netrin-1.
supported_by:
- reference_id: PMID:22685302
supporting_text: Netrin-1 induces axon growth cone collapse of mouse cerebellum external granule
layer (EGL) cells
- term:
id: GO:0045202
label: synapse
evidence_type: IEA
original_reference_id: GO_REF:0000044
review:
summary: UniProt indicates DSCAM is localized to "Synapse." DSCAM promotes lamina-specific synaptic
connections in the retina and is found at the dendritic spine postsynaptic density [PMID:35914814].
action: ACCEPT
reason: Synaptic localization is consistent with DSCAM's function in promoting synaptic connectivity
via homophilic interactions, particularly in the retina. Recent work identified DSCAM at the postsynaptic
density.
supported_by:
- reference_id: PMID:35914814
supporting_text: some of the proteins encoded by HSA21 were located at the dendritic spine postsynaptic
density
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:32296183
review:
summary: From HuRI (Human Reference Interactome) high-throughput Y2H screening. The term "protein
binding" is uninformative for DSCAM which has well-characterized specific binding partners including
NTN1, DCC, UNC5C, DLG2, and PIH1D2.
action: MARK_AS_OVER_ANNOTATED
reason: While DSCAM does bind proteins, this generic term provides no functional insight. The HuRI
study is a systematic proteome-wide screen that detected many interactions but "protein binding"
as an MF term is too vague to be useful for DSCAM annotation. More specific terms like "cell-cell
adhesion mediator activity" or "netrin receptor binding" are more informative.
supported_by:
- reference_id: PMID:32296183
supporting_text: Apr 8. A reference map of the human binary protein interactome.
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:32822567
review:
summary: From a high-throughput IgSF cell-surface interactome study. This generic term does not capture
the specific functional interactions of DSCAM.
action: MARK_AS_OVER_ANNOTATED
reason: Same rationale as other protein binding annotations. High-throughput screens correctly detect
that DSCAM binds proteins, but the GO term is uninformative. More specific molecular function terms
are preferred.
supported_by:
- reference_id: PMID:32822567
supporting_text: A Human IgSF Cell-Surface Interactome Reveals a Complex Network of Protein-Protein
Interactions.
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:35914814
review:
summary: From chromosome 21 protein-protein interaction study identifying DSCAM interactions with
DLGs and DYRK1A at the postsynaptic density [PMID:35914814].
action: MARK_AS_OVER_ANNOTATED
reason: While this study provides useful functional context (DSCAM-DLG and DSCAM-DYRK1A interactions
at postsynapse), the generic "protein binding" term is uninformative. The specific finding about
DLG binding would be better captured by a more specific term if available.
supported_by:
- reference_id: PMID:35914814
supporting_text: an intracellular domain of DSCAM bound either DLGs, which are multimeric scaffolds
comprising receptors, ion channels and associated signaling proteins, or DYRK1A
- term:
id: GO:0007162
label: negative regulation of cell adhesion
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: DSCAM mediates repulsion between neuronal processes through homophilic interactions, leading
to self-avoidance. UniProt states DSCAM "Promotes repulsion between specific neuronal processes
of either the same cell or the same subtype of cells."
action: ACCEPT
reason: This annotation captures DSCAM's role in neuronal self-avoidance through homophilic repulsion.
While DSCAM promotes initial adhesion, the functional outcome is repulsion and negative regulation
of further adhesion between sister processes.
- term:
id: GO:0007411
label: axon guidance
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: Duplicate annotation with different evidence code. Axon guidance is a core function of DSCAM
already reviewed with IBA evidence.
action: ACCEPT
reason: Duplicate annotation supporting the core function. Axon guidance via netrin-1 signaling is
well-established for DSCAM.
- term:
id: GO:0038007
label: netrin-activated signaling pathway
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: DSCAM functions as a netrin receptor and mediates netrin-activated signaling. Upon binding
netrin-1, DSCAM activates downstream signaling including MAPK8 and p38 MAP kinase [PMID:18585357,
PMID:19196994].
action: ACCEPT
reason: This is a core function of DSCAM as a netrin receptor. DSCAM mediates intracellular signaling
by stimulating activation of MAPK8 and MAP kinase p38 in response to netrin-1 binding.
supported_by:
- reference_id: PMID:19196994
supporting_text: DSCAM by itself, in the absence of DCC, is capable of mediating netrin signaling
in activating phosphorylation of Fyn and Pak1
- term:
id: GO:0043025
label: neuronal cell body
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: Duplicate annotation with different evidence code. Neuronal cell body localization already
reviewed with IBA evidence.
action: ACCEPT
reason: Duplicate annotation supporting DSCAM localization to soma of neurons.
- term:
id: GO:0048842
label: positive regulation of axon extension involved in axon guidance
evidence_type: IEA
original_reference_id: GO_REF:0000120
review:
summary: Duplicate annotation with different evidence code. This core function already reviewed with
IBA evidence.
action: ACCEPT
reason: Duplicate annotation. DSCAM promotes axon extension in response to netrin-1 during commissural
axon guidance.
- term:
id: GO:0070593
label: dendrite self-avoidance
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: Duplicate annotation with different evidence code. Dendrite self-avoidance already reviewed
with IBA evidence.
action: ACCEPT
reason: Duplicate annotation. DSCAM contributes to dendrite self-avoidance in vertebrates, particularly
in retinal neurons.
- term:
id: GO:1990782
label: protein tyrosine kinase binding
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: DSCAM interacts with tyrosine kinases including FYN and FAK. UniProt states DSCAM "Interacts
with PTK2" (FAK) and "Interacts with FYN." DSCAM is phosphorylated at tyrosine residues, and this
is enhanced by netrin-1.
action: ACCEPT
reason: DSCAM binding to protein tyrosine kinases is supported by UniProt annotations describing interactions
with PTK2 (FAK) and FYN. Netrin-1 enhances DSCAM tyrosine phosphorylation, suggesting functional
relevance of these interactions.
supported_by:
- reference_id: PMID:22685302
supporting_text: Netrin-1 increases tyrosine phosphorylation of endogenous DSCAM, UNC5C, FAK, Fyn,
and PAK1, and promotes complex formation of DSCAM with these signaling molecules
- term:
id: GO:1990890
label: netrin receptor binding
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: GO:1990890 "netrin receptor binding" means binding TO a netrin receptor. DSCAM binds to UNC5C
and DCC, both of which are netrin receptors [PMID:22685302]. DSCAM also interacts with DCC via its
transmembrane domain, and this interaction is abolished in response to NTN1 (UniProt). The IEA annotation
is propagated from mouse Dscam (Q9ERC8) which was experimentally demonstrated to bind UNC5C.
action: ACCEPT
reason: DSCAM does bind to other netrin receptors (UNC5C and DCC), making "netrin receptor binding"
a correct annotation. PMID:22685302 demonstrated that DSCAM interacts with UNC5C and this interaction
is stimulated by netrin-1. UniProt confirms DSCAM interacts with DCC. Note that DSCAM itself is
ALSO a netrin receptor, but this term captures its ability to bind other netrin receptors, which
is functionally important for coordinating attractive and repulsive guidance responses.
supported_by:
- reference_id: PMID:22685302
supporting_text: DSCAM interacts with UNC5C and this interaction is stimulated by netrin-1 in primary
cortical neurons and postnatal cerebellar granule cells
- term:
id: GO:0007411
label: axon guidance
evidence_type: ISS
original_reference_id: GO_REF:0000024
review:
summary: Duplicate annotation with ISS evidence. Axon guidance is a core function of DSCAM already
reviewed multiple times with IBA and IEA evidence.
action: ACCEPT
reason: ISS (Inferred from Sequence Similarity) annotation supporting the well-established core function.
Multiple evidence codes for the same term are acceptable.
- term:
id: GO:0030425
label: dendrite
evidence_type: ISS
original_reference_id: GO_REF:0000024
review:
summary: Duplicate annotation with ISS evidence. Dendrite localization already reviewed with IEA evidence.
action: ACCEPT
reason: ISS annotation supporting dendritic localization, consistent with DSCAM's role in dendrite
self-avoidance.
- term:
id: GO:0043025
label: neuronal cell body
evidence_type: ISS
original_reference_id: GO_REF:0000024
review:
summary: Duplicate annotation with ISS evidence. Neuronal cell body localization already reviewed
with IBA and IEA evidence.
action: ACCEPT
reason: ISS annotation supporting soma localization. Multiple evidence codes acceptable.
- term:
id: GO:1990890
label: netrin receptor binding
evidence_type: IPI
original_reference_id: PMID:22685302
review:
summary: This annotation refers to DSCAM binding to UNC5C, which is a netrin receptor. PMID:22685302
demonstrates that "DSCAM interacts with UNC5C and this interaction is stimulated by netrin-1." However,
DSCAM itself IS also a netrin receptor.
action: ACCEPT
reason: Unlike the IEA annotation for this term, this IPI annotation from PMID:22685302 correctly
captures that DSCAM binds to UNC5C (a netrin receptor) in the context of netrin-1 mediated growth
cone collapse. DSCAM associates with UNC5C to coordinate netrin-1 repulsion signaling.
supported_by:
- reference_id: PMID:22685302
supporting_text: DSCAM interacts with UNC5C and this interaction is stimulated by netrin-1 in primary
cortical neurons and postnatal cerebellar granule cells
- term:
id: GO:0007156
label: homophilic cell-cell adhesion
evidence_type: ISS
original_reference_id: GO_REF:0000024
review:
summary: Duplicate annotation with ISS evidence. Homophilic cell-cell adhesion already reviewed with
IBA evidence.
action: ACCEPT
reason: ISS annotation supporting the core homophilic adhesion function. Multiple evidence codes acceptable.
- term:
id: GO:0007416
label: synapse assembly
evidence_type: ISS
original_reference_id: GO_REF:0000024
review:
summary: DSCAM promotes lamina-specific synaptic connections via homophilic interactions. UniProt
describes DSCAM as an "Adhesion molecule that promotes lamina-specific synaptic connections in the
retina."
action: KEEP_AS_NON_CORE
reason: While DSCAM contributes to synaptic connectivity through promoting lamina-specific connections,
synapse assembly is not the primary function. The core functions are netrin receptor-mediated axon
guidance and neuronal self-avoidance. Synapse assembly is a downstream consequence of DSCAM's adhesion
properties.
- term:
id: GO:0010842
label: retina layer formation
evidence_type: ISS
original_reference_id: GO_REF:0000024
review:
summary: DSCAM functions in retinal development, particularly in maintaining mosaic spacing between
amacrine and ganglion cells and promoting lamina-specific connections.
action: KEEP_AS_NON_CORE
reason: Retina layer formation represents a tissue-specific manifestation of DSCAM's general self-avoidance
function. While supported by evidence from mouse studies, this is not a core molecular function
but rather a developmental process in a specific tissue context.
- term:
id: GO:0045202
label: synapse
evidence_type: ISS
original_reference_id: GO_REF:0000024
review:
summary: Duplicate annotation with ISS evidence. Synapse localization already reviewed with IEA evidence.
action: ACCEPT
reason: ISS annotation supporting synaptic localization. Consistent with DSCAM's role in promoting
synaptic connectivity and its localization at the postsynaptic density [PMID:35914814].
- term:
id: GO:0060219
label: camera-type eye photoreceptor cell differentiation
evidence_type: ISS
original_reference_id: GO_REF:0000024
review:
summary: This annotation is based on sequence similarity to mouse Dscam. DSCAM is expressed in retinal
ganglion cells and amacrine cells, and functions in retinal development.
action: KEEP_AS_NON_CORE
reason: Photoreceptor cell differentiation represents a tissue-specific developmental role. This is
not a core function of DSCAM but rather reflects its expression and function in retinal development,
likely through its self-avoidance mechanisms.
- term:
id: GO:0005886
label: plasma membrane
evidence_type: ISS
original_reference_id: GO_REF:0000024
review:
summary: Duplicate annotation with ISS evidence. Plasma membrane localization already reviewed with
IBA, IEA, and TAS evidence.
action: ACCEPT
reason: ISS annotation supporting membrane localization. Multiple evidence codes acceptable.
- term:
id: GO:0007162
label: negative regulation of cell adhesion
evidence_type: ISS
original_reference_id: GO_REF:0000024
review:
summary: Duplicate annotation with ISS evidence. Negative regulation of cell adhesion already reviewed
with IEA evidence.
action: ACCEPT
reason: ISS annotation supporting DSCAM's role in neuronal self-avoidance/repulsion.
- term:
id: GO:0030424
label: axon
evidence_type: ISS
original_reference_id: GO_REF:0000024
review:
summary: Duplicate annotation with ISS evidence. Axon localization already reviewed with IBA and IEA
evidence.
action: ACCEPT
reason: ISS annotation supporting axonal localization. Multiple evidence codes acceptable.
- term:
id: GO:0030426
label: growth cone
evidence_type: ISS
original_reference_id: GO_REF:0000024
review:
summary: Duplicate annotation with ISS evidence. Growth cone localization already reviewed with IEA
evidence.
action: ACCEPT
reason: ISS annotation supporting growth cone localization. Consistent with DSCAM's function in netrin-1-mediated
growth cone guidance.
- term:
id: GO:0070593
label: dendrite self-avoidance
evidence_type: ISS
original_reference_id: GO_REF:0000024
review:
summary: Duplicate annotation with ISS evidence. Dendrite self-avoidance already reviewed with IBA
and IEA evidence.
action: ACCEPT
reason: ISS annotation supporting dendrite self-avoidance function. Multiple evidence codes acceptable.
- term:
id: GO:0048842
label: positive regulation of axon extension involved in axon guidance
evidence_type: IDA
original_reference_id: PMID:18585357
review:
summary: IDA (Inferred from Direct Assay) annotation from PMID:18585357 which demonstrated that DSCAM
is a netrin receptor necessary for commissural axons to grow toward and across the midline. DSCAM
mediates turning responses to netrin-1.
action: ACCEPT
reason: This is a high-quality experimental annotation for a core function. The Cell paper demonstrated
that DSCAM and DCC can each mediate turning responses to netrin-1, and DSCAM is necessary for commissural
axon guidance.
supported_by:
- reference_id: PMID:18585357
supporting_text: DSCAM is a receptor that can mediate turning responses to netrin-1 and support
a key role for netrin/DSCAM signaling in commissural axon guidance in vertebrates
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:19196994
review:
summary: IPI annotation based on interaction with NTN1 (netrin-1) demonstrated in PMID:19196994. While
the interaction is real and functionally important, "protein binding" is too generic for this well-characterized
receptor-ligand interaction.
action: MARK_AS_OVER_ANNOTATED
reason: DSCAM binding to netrin-1 is a specific receptor-ligand interaction that should be annotated
with a more specific term. The generic "protein binding" term is uninformative when the specific
interaction partner (NTN1) is known.
supported_by:
- reference_id: PMID:19196994
supporting_text: DSCAM is expressed on commissural axons and interacts with Netrin-1, a prototypical
guidance cue for commissural axons
- term:
id: GO:0042327
label: positive regulation of phosphorylation
evidence_type: IDA
original_reference_id: PMID:19196994
review:
summary: PMID:19196994 demonstrated that DSCAM mediates netrin signaling by activating phosphorylation
of Fyn and Pak1. "DSCAM by itself, in the absence of DCC, is capable of mediating netrin signaling
in activating phosphorylation of Fyn and Pak1."
action: ACCEPT
reason: This is a well-supported IDA annotation. The study demonstrated that DSCAM promotes phosphorylation
of downstream signaling molecules (Fyn, Pak1) in response to netrin-1, representing a key signaling
output of DSCAM receptor activity.
supported_by:
- reference_id: PMID:19196994
supporting_text: DSCAM by itself, in the absence of DCC, is capable of mediating netrin signaling
in activating phosphorylation of Fyn and Pak1
- term:
id: GO:0005886
label: plasma membrane
evidence_type: TAS
original_reference_id: Reactome:R-HSA-376122
review:
summary: TAS annotation from Reactome pathway for DSCAM/DSCAML1 homodimerization, which occurs at
the plasma membrane.
action: ACCEPT
reason: Duplicate annotation supporting membrane localization. The Reactome pathway correctly captures
DSCAM homodimerization at the cell surface.
- term:
id: GO:0005886
label: plasma membrane
evidence_type: TAS
original_reference_id: PMID:9426258
review:
summary: TAS annotation from the original DSCAM cloning paper which described the transmembrane domain
topology.
action: ACCEPT
reason: Duplicate annotation from the original characterization paper supporting plasma membrane localization
of the Long isoform.
supported_by:
- reference_id: PMID:9426258
supporting_text: both containing 10 Ig-C2 domains... with or without the following transmembrane
and intracellular domains
- term:
id: GO:0007155
label: cell adhesion
evidence_type: TAS
original_reference_id: PMID:9426258
review:
summary: TAS annotation from the original DSCAM cloning paper which described DSCAM as a novel cell
adhesion molecule of the immunoglobulin superfamily.
action: ACCEPT
reason: Duplicate annotation supporting cell adhesion function from the original characterization
paper.
supported_by:
- reference_id: PMID:9426258
supporting_text: a novel member of the immunoglobulin (Ig) superfamily that represents a new class
of neural cell adhesion molecules
- term:
id: GO:0007399
label: nervous system development
evidence_type: TAS
original_reference_id: PMID:9426258
review:
summary: TAS annotation from the original paper which established DSCAM expression in the nervous
system during neural differentiation.
action: ACCEPT
reason: Duplicate annotation supporting nervous system development function from the original characterization
paper.
supported_by:
- reference_id: PMID:9426258
supporting_text: DSCAM is involved in neural differentiation and contributes to the central and
peripheral nervous system defects in DS
- term:
id: GO:0016020
label: membrane
evidence_type: TAS
original_reference_id: PMID:9426258
review:
summary: TAS annotation from the original paper. GO:0016020 (membrane) is a parent term of GO:0005886
(plasma membrane), which is already well-annotated for DSCAM.
action: ACCEPT
reason: While this is a broader term than plasma membrane (already annotated), it is accurate for
the Long isoform. The original paper described the transmembrane domain structure.
supported_by:
- reference_id: PMID:9426258
supporting_text: 'DSCAM: a novel member of the immunoglobulin superfamily maps in a Down syndrome
region and is involved in the development of the nervous system.'
references:
- id: GO_REF:0000024
title: Manual transfer of experimentally-verified manual GO annotation data to orthologs by curator
judgment of sequence similarity
findings: []
- id: GO_REF:0000033
title: Annotation inferences using phylogenetic trees
findings: []
- id: GO_REF:0000043
title: Gene Ontology annotation based on UniProtKB/Swiss-Prot keyword mapping
findings: []
- id: GO_REF:0000044
title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping,
accompanied by conservative changes to GO terms applied by UniProt
findings: []
- id: GO_REF:0000107
title: Automatic transfer of experimentally verified manual GO annotation data to orthologs using Ensembl
Compara
findings: []
- id: GO_REF:0000120
title: Combined Automated Annotation using Multiple IEA Methods
findings: []
- id: PMID:9426258
title: 'DSCAM: a novel member of the immunoglobulin superfamily maps in a Down syndrome region and is
involved in the development of the nervous system.'
findings:
- statement: DSCAM is a novel IgSF cell adhesion molecule with 10 Ig-C2 domains and 6 FNIII domains,
existing as two isoforms (Long with transmembrane domain, Short without), expressed primarily in
brain during neuronal differentiation.
supporting_text: The sequence of cDNAs indicates alternative splicing and predicts two protein isoforms,
both containing 10 Ig-C2 domains...with or without the following transmembrane and intracellular
domains
- id: PMID:10925149
title: Down syndrome cell adhesion molecule DSCAM mediates homophilic intercellular adhesion.
findings:
- statement: DSCAM mediates homophilic intercellular adhesion as demonstrated by cell aggregation assays.
- id: PMID:18585357
title: DSCAM is a netrin receptor that collaborates with DCC in mediating turning responses to netrin-1.
findings:
- statement: DSCAM is expressed on spinal commissural axons, binds netrin-1, and is necessary for commissural
axons to grow toward and across the midline. DSCAM and DCC can each mediate a turning response to
netrin-1 independently.
supporting_text: the Down's syndrome Cell Adhesion Molecule (DSCAM) ...is expressed on spinal commissural
axons, binds netrin-1, and is necessary for commissural axons to grow toward and across the midline.
DSCAM and DCC can each mediate a turning response of these neurons to netrin-1
- id: PMID:19196994
title: DSCAM functions as a netrin receptor in commissural axon pathfinding.
findings:
- statement: DSCAM interacts with Netrin-1 and independently of DCC mediates netrin signaling by activating
phosphorylation of Fyn and Pak1. Knockdown causes commissural axon projection and pathfinding defects.
supporting_text: DSCAM by itself, in the absence of DCC, is capable of mediating netrin signaling
in activating phosphorylation of Fyn and Pak1
- id: PMID:22685302
title: Down syndrome cell adhesion molecule (DSCAM) associates with uncoordinated-5C (UNC5C) in netrin-1-mediated
growth cone collapse.
findings:
- statement: DSCAM interacts with UNC5C in a netrin-1-stimulated manner and coordinates with UNC5C in
netrin-1-mediated growth cone collapse (repulsion). Netrin-1 increases tyrosine phosphorylation
of DSCAM, UNC5C, FAK, Fyn, and PAK1 and promotes complex formation.
supporting_text: DSCAM interacts with UNC5C and this interaction is stimulated by netrin-1 in primary
cortical neurons and postnatal cerebellar granule cells
- id: PMID:32296183
title: A reference map of the human binary protein interactome.
findings:
- statement: High-throughput Y2H interactome study (HuRI) identifying binary protein-protein interactions
including DSCAM-PIH1D2.
- id: PMID:32822567
title: A Human IgSF Cell-Surface Interactome Reveals a Complex Network of Protein-Protein Interactions.
findings:
- statement: Systematic IgSF cell-surface interactome study detecting DSCAM interactions with multiple
cell-surface proteins.
- id: PMID:35914814
title: 'Chr21 protein-protein interactions: enrichment in proteins involved in intellectual disability,
autism, and late-onset Alzheimer''s disease.'
findings:
- statement: DSCAM intracellular domain binds DLG2 (scaffold at postsynaptic density) and DYRK1A. Some
HSA21 proteins including DSCAM were located at the dendritic spine postsynaptic density.
supporting_text: an intracellular domain of DSCAM bound either DLGs, which are multimeric scaffolds
comprising receptors, ion channels and associated signaling proteins, or DYRK1A
- id: Reactome:R-HSA-376122
title: DSCAM/DSCAML1 homodimerization
findings:
- statement: DSCAM and DSCAML1 proteins are involved in homophilic intercellular interactions. DSCAM
uses homophilic repulsion to promote both self-avoidance and tiling of neuronal receptive fields.
core_functions:
- molecular_function:
id: GO:0098632
label: cell-cell adhesion mediator activity
description: DSCAM functions as a receptor for netrin-1 (NTN1) via Ig-like domains 7-9, mediating turning
responses and axon extension during commissural axon guidance. DSCAM also forms homodimers mediating
homophilic cell-cell adhesion, which underlies neuronal self-avoidance where recognition leads to
repulsion between sister neuronal processes.
directly_involved_in:
- id: GO:0007411
label: axon guidance
- id: GO:0038007
label: netrin-activated signaling pathway
- id: GO:0070593
label: dendrite self-avoidance
locations:
- id: GO:0005886
label: plasma membrane
- id: GO:0030424
label: axon
- id: GO:0030426
label: growth cone
supported_by:
- reference_id: PMID:18585357
supporting_text: DSCAM is a receptor that can mediate turning responses to netrin-1 and support a
key role for netrin/DSCAM signaling in commissural axon guidance in vertebrates
- reference_id: PMID:19196994
supporting_text: DSCAM functions as a netrin receptor in commissural axon pathfinding
alternative_products:
- name: Long (CHD2-42)
id: O60469-1
description: 'The canonical long isoform. Contains 10 Ig domains and 6 fibronectin type III domains.
Functions in neuronal self-avoidance and axon guidance. CRITICAL NOTE: Unlike Drosophila Dscam1 which
has 38,016 isoforms via mutually exclusive splicing, human DSCAM has only 2 isoforms. Vertebrates
achieve neuronal diversity through clustered protocadherins instead.'
- name: Short (CHD2-52)
id: O60469-2
sequence_note: VSP_002502, VSP_002503
description: A shorter isoform with alternative C-terminus. Less well characterized than the long isoform.
The functional significance of this isoform versus the long form is not well established in the literature.