NT1 (DNT1, Spรคtzle 2) encodes Drosophila neurotrophin 1, a secreted Spรคtzle-family cystine-knot protein made as a prepro-protein that is cleaved by furins and released both full length and as mature cystine-knot forms. It is expressed at the embryonic CNS midline, in muscles and in the adult brain. DNT1 binds the Toll-family receptors Toll-7 and Toll-6, which act as neurotrophin receptors; mature DNT1 activates NF-kappaB (Dorsal/Dif) and ERK signaling to promote neuronal survival, whereas pro-DNT1 can activate pro-apoptotic JNK signaling. DNT1 maintains neuronal survival non-autonomously in the embryonic CNS, is needed for motor axon targeting, and with DNT2 contributes to synaptogenesis at the larval neuromuscular junction. It also binds the Trk-like Kek-6, and in the larval trachea it is the proposed ligand of Toll-8/Tollo in a module that dampens antimicrobial peptide expression.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005121 Toll binding | IBA GO_REF:0000033 | MODIFY | Summary: IBA from PAINT node PTN002354018 (PTHR23199), seeded by spz, spz5, spz6 and NT1 itself. DNT1 does bind Toll-family receptors (Toll-7, Toll-6, and Toll-1 in vitro), so the binding claim is true and inherited across the Spรคtzle/DNT clade. Reason: DNT1 is a secreted ligand, and the binding is how it activates its receptors. Under the project ligand convention (projects/LIGANDS_IN_SIGNALING.md) a ligand's molecular function is receptor ligand activity or a child, not a receptor-specific binding term. The PAINT node already carries growth factor activity (GO:0008083), a child of receptor ligand activity, which fits a neurotrophin; it is the replacement. The node placement itself is sound: NT1 is inside the clade and has its own binding evidence. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: PANTHER:PTN002354018 SUPPORTS TRANSFER The node is seeded by experimental Toll-binding annotations of spz, spz5, spz6 and NT1; the binding claim transfers correctly, but for ligands the ligand-activity term carried by the same node (growth factor activity) is the appropriate MF. Proposed replacements: growth factor activity Supporting Evidence: PMID:23892553 Together, these data demonstrate that DNT1 binds Toll-7 and DNT2 binds promiscuously Toll-6 and Toll-7. PMID:19018662 show that DNT1 promotes cell survival nonautonomously in the CNS |
| GO:0005121 Toll binding | IDA PMID:31088910 Toll family members bind multiple Spรคtzle proteins and activ... | MODIFY | Summary: Co-IP in S2 cells: the DNT1 (Spz-2) cystine knot binds the Toll-1 and Toll-7 ectodomains (Chowdhury et al. 2019). Toll-7 binding was shown earlier in vitro and in vivo (PMID:23892553). Reason: The interaction is real, but it is the binding step of a ligand activity. Following the ligand convention, receptor-specific binding terms on ligands are replaced by receptor ligand activity; this paper shows binding plus reporter activation, which supports receptor ligand activity (GO:0048018), already carried by this gene from the same paper. The split from the IBA row (replaced by its child, growth factor activity) is deliberate; each row is refined to what its own evidence shows, and this reporter assay has no growth or survival readout. Proposed replacements: receptor ligand activity Supporting Evidence: PMID:31088910 Focusing on Toll-1 and Toll-7, our co-IP assays indicate the ectodomains of each bind Spz-1, -2, and -5, but not other family members, while also suggesting that binding of Spz-1, -2, and -5 to full-length Toll-1 or Toll-7 results in activation of the drosomycin promoter. PMID:23892553 Together, these data demonstrate that DNT1 binds Toll-7 and DNT2 binds promiscuously Toll-6 and Toll-7. |
| GO:0005576 extracellular region | IBA GO_REF:0000033 | ACCEPT | Summary: IBA from PTN002354018: all Spรคtzle-family members are secreted cystine-knot proteins. Reason: DNT1 has a signal peptide and is secreted from cells as full-length and cleaved forms; it acts non-autonomously on neurons. The extracellular location is inherited across the family and is correct for NT1. Supporting Evidence: PMID:23892553 DNT1 is secreted both as full-length and mature forms PMID:19018662 show that DNT1 promotes cell survival nonautonomously in the CNS |
| GO:0005576 extracellular region | IDA PMID:31088910 Toll family members bind multiple Spรคtzle proteins and activ... | ACCEPT | Summary: Cystine-knot domains of the Spz proteins, including Spz-2/DNT1, were expressed as secreted proteins and recovered from S2 cell culture medium for binding assays. Reason: Secretion is independently shown by McIlroy et al. (2013) and Foldi et al. (2017); DNT1 is an extracellular ligand. Supporting Evidence: PMID:23892553 DNT1 is secreted both as full-length and mature forms PMID:28373203 DNT1 and 2 are cleaved intracellularly by conserved furins. |
| GO:0005576 extracellular region | IEA GO_REF:0000117 | ACCEPT | Summary: ARBA electronic mapping to extracellular region. Reason: Correct, consistent with experimental secretion data for DNT1. Supporting Evidence: PMID:23892553 DNT1 is secreted both as full-length and mature forms |
| GO:0008045 motor neuron axon guidance | IMP PMID:19018662 Drosophila neurotrophins reveal a common mechanism for nervo... | ACCEPT | Summary: DNT1 mutants and targeted RNAi/overexpression in muscle cause ISNb/d and SN motor axon misrouting in stage 17 embryos (Zhu et al. 2008). Reason: Motor axon targeting is one of the two principal neurotrophic outputs of DNT1, together with neuronal survival, and is also a Toll-7 output (PMID:23892553). The term is as specific as the phenotype allows. Supporting Evidence: PMID:19018662 In all cases, there is a significant increase in the incidence of misrouting phenotypes in ISNb/d and SN fascicles compared to wild type PMID:23892553 Toll-6 and Toll-7 are expressed in the CNS throughout development and regulate locomotion, motor axon targeting and neuronal survival |
| GO:0008063 Toll signaling pathway | IDA PMID:31088910 Toll family members bind multiple Spรคtzle proteins and activ... | MODIFY | Summary: Chowdhury et al. (2019) showed that the DNT1 (Spz-2) cystine knot activates a drosomycin reporter in S2 cells expressing full-length Toll-1 or Toll-7. Reason: GO:0008063 is defined by ligand binding to the receptor Toll (Toll-1), the immune and dorsal-ventral pathway. For DNT1 the Toll-1 arm rests only on an over-expression reporter assay in S2 cells; no in vivo study places DNT1 in Toll-1 signaling. The Toll-7 arm of the same assay, and the in vivo genetic and signaling work (McIlroy et al. 2013; Foldi et al. 2017), show DNT1 activating Toll-7/Toll-6 as a neurotrophin, which is the neurotrophin signaling pathway (GO:0038179). As a ligand, DNT1 is part of the pathway it initiates (projects/LIGANDS_IN_SIGNALING.md). Proposed replacements: neurotrophin signaling pathway Supporting Evidence: PMID:31088910 As noted previously, Toll-6 and Toll-7 function as neurotrophin receptors in the central nervous system with Spz-2 and Spz-5 being candidate ligands for both PMID:23892553 Over-expression of Toll-7CY in all neurons rescued the apoptosis caused by loss of DNT1 function PMID:28373203 Collectively, these data show that DNT1 and 2 can activate the prosurvival signaling pathways NF-ฮบB and ERK via Toll-6 and -7 and that pro-DNT1 can activate the proapoptotic JNK pathway. |
| GO:0008083 growth factor activity | IBA GO_REF:0000033 | ACCEPT | Summary: IBA from PTN002354018, seeded by spz, spz5 and NT1 experimental annotations. Reason: Growth factor activity is a child of receptor ligand activity and is the best-fitting ligand-activity term for a neurotrophin that promotes neuronal survival and growth. NT1 is within the clade and has its own experimental support. Supporting Evidence: PMID:19018662 show that DNT1 promotes cell survival nonautonomously in the CNS PMID:23892553 Together, these data demonstrate that DNT1 binds Toll-7 and DNT2 binds promiscuously Toll-6 and Toll-7. |
| GO:0008083 growth factor activity | IMP PMID:19018662 Drosophila neurotrophins reveal a common mechanism for nervo... | ACCEPT | Summary: Loss and gain of DNT1 function show it is a trophic factor maintaining neuronal survival non-autonomously (Zhu et al. 2008). Reason: Core molecular function: DNT1 is a secreted neurotrophic ligand acting on Toll-7/Toll-6. Growth factor activity is a child of receptor ligand activity and is the most specific ligand term available for a neurotrophin. Supporting Evidence: PMID:19018662 show that DNT1 promotes cell survival nonautonomously in the CNS PMID:19018662 Thus, DNT1 presents structural, cleavage, and dimerising features of canonical NTs. PMID:23892553 Together, these data demonstrate that DNT1 binds Toll-7 and DNT2 binds promiscuously Toll-6 and Toll-7. |
| GO:0021556 central nervous system formation | IBA GO_REF:0000033 | MARK AS OVER ANNOTATED | Summary: IBA from PTN002354018, seeded by NT1 and spz5 IMP rows from Zhu et al. (2008). Reason: The seed annotations rest on the title-level claim of Zhu et al. (2008). The phenotypes are late neuronal apoptosis and motor axon misrouting, not a failure to form the CNS; DNT1 mutants have normal CNS apoptosis and no guidance defects at stages 13/14 and no massive neuronal death. The specific outputs are captured by negative regulation of neuron apoptotic process and motor neuron axon guidance. Propagation Review Root cause: SOURCE WEAK OR INFERRED Failure modes: SOURCE EVIDENCE WEAK GRANULARITY MISMATCH Sources checked: PANTHER:PTN002354018 SOURCE WEAK OR INFERRED The IBD for central nervous system formation is seeded only by the NT1 and spz5 IMP rows from Zhu et al. 2008, whose phenotypes are late neuronal apoptosis and axon misrouting rather than failed CNS formation. Supporting Evidence: PMID:19018662 In the CNS of homozygous DNT141 null mutant embryos, apoptosis levels are comparable to wild type at stages 13/14, and there are no axon guidance defects (unpublished data). PMID:19018662 Loss of DNT1, spz, Toll, or DNT2 function does not cause massive CNS neuronal death either. |
| GO:0021556 central nervous system formation | IMP PMID:19018662 Drosophila neurotrophins reveal a common mechanism for nervo... | MARK AS OVER ANNOTATED | Summary: Zhu et al. (2008) describe DNT1 loss-of-function phenotypes in the embryonic CNS: increased apoptosis and motor axon misrouting. Reason: Central nervous system formation overstates the phenotype. The CNS forms normally in DNT1 mutants; the defects are increased late neuronal death and motor axon targeting errors, which are annotated with specific terms. Supporting Evidence: PMID:19018662 In the CNS of homozygous DNT141 null mutant embryos, apoptosis levels are comparable to wild type at stages 13/14, and there are no axon guidance defects (unpublished data). PMID:19018662 Loss of DNT1, spz, Toll, or DNT2 function does not cause massive CNS neuronal death either. |
| GO:0031637 regulation of neuronal synaptic plasticity in response to neurotrophin | IMP PMID:19018662 Drosophila neurotrophins reveal a common mechanism for nervo... | KEEP AS NON CORE | Summary: Annotated from Zhu et al. (2008), which shows survival and targeting phenotypes and only speculates about synaptic plasticity. Sutcliffe et al. (2013) later showed that DNT1 and DNT2 together are required at the larval NMJ for synaptogenesis and normal bouton number. Reason: The cited paper does not itself test synaptic plasticity, but the claim is supported by later NMJ work in which DNT1 acts redundantly with DNT2 as a muscle-derived retrograde factor. Synaptic roles are better established for DNT2 (PMID:28846707) than for DNT1, so the term is kept as non-core for NT1. Supporting Evidence: PMID:24124519 Our data indicate that DNTs are produced in muscle and are required in neurons for synaptogenesis. PMID:24124519 DNT1 and DNT2 function together at the muscles 6,7 NMJ PMID:24124519 Most likely alterations in DNT function and synapse formation induce NMJ plasticity leading to homeostatic adjustments that increase terminal size restoring overall synaptic transmission. |
| GO:0043524 negative regulation of neuron apoptotic process | IDA PMID:19018662 Drosophila neurotrophins reveal a common mechanism for nervo... | ACCEPT | Summary: Expression of the DNT1 cystine knot reduces naturally occurring neuronal apoptosis, and DNT1 mutants have increased CNS apoptosis rescued by DNT1 (Zhu et al. 2008). Reason: Neuronal survival is the core neurotrophic output of DNT1, acting via Toll-7 (rescue of DNT1 mutant apoptosis by activated Toll-7) and NF-kB. Supporting Evidence: PMID:19018662 show that DNT1 promotes cell survival nonautonomously in the CNS PMID:23892553 Over-expression of Toll-7CY in all neurons rescued the apoptosis caused by loss of DNT1 function PMID:28373203 Collectively, these data show that DNT1 and 2 can activate the prosurvival signaling pathways NF-ฮบB and ERK via Toll-6 and -7 and that pro-DNT1 can activate the proapoptotic JNK pathway. |
| GO:0045087 innate immune response | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: IBA from PTN002354018 seeded by spz and spz5. Reason: DNT1 has some immune-related evidence: it is the proposed ligand of Toll-8/Tollo in a tracheal module that dampens antimicrobial peptide expression (Akhouayri et al. 2011), and its cystine knot can activate Toll-1/Toll-7 reporter activity in S2 cells. The family-level inheritance of an immune role is plausible, but DNT1's main established function is neurotrophic, so this is non-core. Supporting Evidence: PMID:22022271 This IMD-dependent AMP activation is antagonized by a constitutively active signalling module involving the receptor Toll-8/Tollo, the ligand Spรคtzle2/DNT1 and Ect-4 PMID:31088910 Focusing on Toll-1 and Toll-7, our co-IP assays indicate the ectodomains of each bind Spz-1, -2, and -5, but not other family members, while also suggesting that binding of Spz-1, -2, and -5 to full-length Toll-1 or Toll-7 results in activation of the drosomycin promoter. |
| GO:0048018 receptor ligand activity | IDA PMID:31088910 Toll family members bind multiple Spรคtzle proteins and activ... | ACCEPT | Summary: DNT1 cystine knot binds Toll-1/Toll-7 ectodomains and activates reporter expression through full-length Toll-1 or Toll-7 in S2 cells. Reason: Receptor ligand activity is the correct ligand MF for this assay, which shows receptor binding plus activation but no growth-promoting output. It covers DNT1's ligand roles for several receptors (Toll-7, Toll-6, Tollo). The more specific growth factor activity is supported for the neurotrophic role by other rows. Supporting Evidence: PMID:31088910 Focusing on Toll-1 and Toll-7, our co-IP assays indicate the ectodomains of each bind Spz-1, -2, and -5, but not other family members, while also suggesting that binding of Spz-1, -2, and -5 to full-length Toll-1 or Toll-7 results in activation of the drosomycin promoter. PMID:23892553 Together, these data demonstrate that DNT1 binds Toll-7 and DNT2 binds promiscuously Toll-6 and Toll-7. |
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