id: MODULE:neurotrophin_toll_signaling title: Neurotrophin signaling through Toll-family receptors module description: >- In Drosophila the secreted cystine-knot neurotrophins DNT1 (NT1, Spz2) and DNT2 (Spz5) act on neurons through the Toll-family receptors Toll-6 and Toll-7 rather than through Trk-family receptor tyrosine kinases. DNT binding to Toll-6 or Toll-7 regulates neuronal survival, motor axon targeting and structural synaptic plasticity; the kinase-less Trk-like receptor Kekkon-6 binds DNT2 and acts together with Toll-6 at synapses. status: DRAFT scope: ABSTRACT evidence: - source_id: GO:0038179 title: neurotrophin signaling pathway statement: The module is grounded in the GO biological process term for neurotrophin signaling, defined as signaling initiated by neurotrophin binding to its receptor on the surface of a target cell. - source_id: PMID:23892553 title: Toll-6 and Toll-7 function as neurotrophin receptors in the Drosophila melanogaster CNS. statement: Identifies Toll-6 and Toll-7 as receptors for the Drosophila neurotrophins DNT1 and DNT2, which bind them promiscuously; used for the two-step ligand/receptor boundary. supporting_text: >- DNT1 (also known as NT1 and spz2) and DNT2 (also known as NT2 and spz5) interact genetically with Toll-6 and Toll-7, and DNT1 and DNT2 bind to Toll-6 and Toll-7 promiscuously - source_id: PMID:19018662 title: Drosophila neurotrophins reveal a common mechanism for nervous system formation. statement: Identifies DNT1 as a Drosophila neurotrophin that maintains neuronal survival and motor axon targeting, and shows that DNT2 and Spz also have neurotrophic functions. supporting_text: >- we show that DNT1 maintains neuronal survival, as more neurons die in DNT1 mutants and expression of DNT1 rescues naturally occurring cell death, and it enables targeting by motor neurons. - source_id: PMID:28373203 title: Three-tier regulation of cell number plasticity by neurotrophins and Tolls in Drosophila. statement: Shows that DNT-Toll signaling can promote either neuronal survival or death depending on ligand cleavage, receptor and downstream adaptor; used to place the adaptor switch at the module boundary. supporting_text: >- Toll-6 promotes cell survival via MyD88-NF-κB and cell death via Wek-Sarm-JNK. notes: >- Boundary. The module has two required steps, a secreted Drosophila neurotrophin (DNT) ligand and a Toll-family neurotrophin receptor on the responding neuron, plus one optional step, the kinase-less Trk-like co-receptor Kekkon-6 (Kek-6), which binds DNT2 and acts with Toll-6 at the neuromuscular junction (PMID:28846707) and in a dopaminergic circuit (PMID:39704728). Kek-6 is optional because Toll-6 and Toll-7 signal without it in the neuronal-survival and axon-targeting assays (PMID:23892553). The intracellular adaptors are not modelled as parts and are recorded here: Toll-6 promotes survival through MyD88 and NF-kappaB (Dorsal, Dif) and death through Weckle (Wek), Sarm (Ect4/dSarm) and JNK, and the outcome also depends on DNT cleavage and on which Toll is engaged (PMID:28373203). These adaptors are shared with Toll-1 and Toll-2 signaling (the MyD88-Tube-Pelle complex is modelled in dmel_toll_signaling), the choice among them is context dependent, and Toll-6/Toll-7 instruct olfactory wiring without their cytoplasmic domains (PMID:25741726), so no single adaptor route is a required step of neurotrophin signaling through Toll receptors. Kek-6 signals through CaMKII and VAP33A rather than through a Toll adaptor (PMID:28846707); those partners are also left out. The immune and dorsal-ventral Spaetzle-Toll-1 pathway (protease cascades, Spz, Toll-1, MyD88-Tube-Pelle, Cactus, Dorsal/Dif) stays in dmel_toll_signaling. Spz5 also activates Toll-1 (PMID:30361090) and acts as a glial Toll-6 ligand released from dying neurons (PMID:30745142); these roles are not neurotrophic and are outside the module. Ligands included and excluded. DNT1 (NT1, UniProtKB:B7TB45) and DNT2 (spz5, UniProtKB:Q9VZX1) are the ligands: both bind Toll-6 and Toll-7 (PMID:23892553). Spaetzle (spz; not to be confused with DNT-3, which is spz3) has neurotrophic functions (PMID:19018662, PMID:24124519) and its cystine-knot domain binds the Toll-7 ectodomain in vitro (PMID:31088910), but its neurotrophic receptor has not been shown to be Toll-6 or Toll-7, and its canonical receptor is Toll-1; it is therefore not a representative member of the ligand step. DNT-3 (spz3) promotes visual-system neuronal survival (PMID:42552905) with no Toll receptor yet assigned. Toll-2 works with DNT-2 in the visual system by genetic interaction (PMID:42552905) and regulates adult brain plasticity (PMID:32066523); because DNT-2 binding to Toll-2 has not been shown biochemically, Toll-2 is recorded here and not added as a receptor representative. The same evidence bar (genetic interaction alone does not make a module member) keeps Multiplexin out of the ligand step of collagen_ddr_signaling. Ligand function term. The ligand step uses GO:0008083 growth factor activity, an is_a child of GO:0048018 receptor ligand activity (verified in QuickGO), following the project decision that a ligand step takes receptor ligand activity or a fitting child. Both DNTs carry GO:0008083 in GOA (IMP, PMID:19018662; IBA from PAINT node PTN002354018) and GO:0048018 (IDA, PMID:31088910; spz5 also IDA PMID:30361090 and IPI PMID:28846707). The receptor-specific GO:0005121 Toll binding, which both DNTs also carry (IDA PMID:31088910 and IBA), is not used. Ligand family and PAINT node. NT1 and spz5 are both in PANTHER:PTHR23199 (NEUROTROPHIN 1-RELATED; UniProt DR PANTHER: NT1 PTHR23199:SF12, spz5 PTHR23199:SF16). The family is broader than the ligand role: it also contains Spaetzle (SF12), Spz3 (SF13), Spz4 (SF5), Spz6 and the horseshoe-crab clotting protein coagulogen (SF12), and UniProt lists members in tardigrades, molluscs and echinoderms. The role is therefore restricted to the DNT1 and DNT2 members. PAINT node PTN002354018 in PTHR23199-paint.tsv carries F:GO:0008083 growth factor activity (seeds FB:FBgn0003495 spz, FB:FBgn0035379 spz5, FB:FBgn0261526 NT1) and F:GO:0005121 Toll binding (same seeds plus FB:FBgn0035056 spz6), and propagates to NT1 and spz5 in GOA (IBA WITH PTN002354018). The node's taxon column is empty in the local table. Receptor family. No PANTHER id is asserted for the receptor step. The two sources disagree on Toll-6: UniProt's cross-reference places Toll-6 (UniProtKB:Q9VUN0) in PTHR24366 (IG(IMMUNOGLOBULIN) AND LRR(LEUCINE RICH REPEAT) DOMAINS), subfamily SF96, while PANTHER's own tree places it in PTHR45836 (SLIT HOMOLOG), subfamily SF8 (TOLL-LIKE RECEPTOR 6), which is why Slit PAINT nodes propagate into it (see below and interpro/panther/PTHR45836/PTHR45836-review.yaml, which lists SF8 among the branches wrongly inheriting Roundabout binding). Which placement is right is not decided here, and no override is recorded. Toll-7 (UniProtKB:Q7KIN0) is in PTHR45712 (AGAP008170-PA), subfamily SF22; neither receptor is in PTHR24365 (TOLL-LIKE RECEPTOR). No PAINT node is shared by the two receptors: the only Toll-7 IBA node, PTN002809265 (F:GO:0038023 signaling receptor activity), is a broad leucine-rich-repeat receptor node placed at Eukaryota whose other seeds are mammalian TLR3, CD180 and related proteins, and Toll-6's IBA rows come from the Slit nodes PTN002911633 (heparin binding, Roundabout binding) and PTN002911625 (axon guidance), which look like over-propagation into a Toll receptor. Neither node is attached to the step. The receptor function is GO:0005030 neurotrophin receptor activity, which GOA gives Toll-6 and Toll-7 by IMP (PMID:23892553) and which the Toll-7 gene review uses as its core function; GO:0005030 is_a GO:0038023 signaling receptor activity and part_of GO:0038179. A Toll-like receptor activity term is not used because Toll-6 and Toll-7 here sense an endogenous growth factor, not a pathogen pattern. Taxon scope. The module is scoped to Drosophila melanogaster (NCBITaxon:7227), the only species in which the ligand-receptor pairing has been tested. Scope criterion, shared with collagen_ddr_signaling: a module takes the taxon of the PAINT nodes that ground its steps; where no PAINT node grounds a step, it takes the clade in which the ligand-receptor pairing has been tested. Here the ligand node has no taxon and no node grounds the receptor step. DNT1 and Spz5 are conserved across insects (PMID:19018662: the DNT1 cystine knot is conserved in mosquitoes, honey bee, jewel wasp and body louse; Spz5 is "very highly conserved in insects"), so the module may extend to Insecta, but no cached paper shows Toll-6/Toll-7 orthologues acting as neurotrophin receptors outside Drosophila, and PAINT gives no taxon for the ligand node. The broader scope is left as a knowledge gap. Relation to vertebrate neurotrophin signaling. The vertebrate pathway (NGF, BDNF, NT-3, NT-4 acting through TRK tyrosine kinases and p75NTR) is modelled in neurotrophin_trk_signaling. The two modules share the GO parent GO:0038179 but not their receptors: Drosophila has no Trk, p75NTR or Sortilin orthologue (PMID:23892553), and its Trk-like Kek proteins lack the kinase domain (PMID:28846707). Zhu et al. propose that DNT1 and the vertebrate neurotrophins share a cystine-knot fold and a common bilaterian ancestor, but they also state that the similarity could be convergent (PMID:19018662). The module therefore does not assert homology between the DNTs and the vertebrate neurotrophins. Annotation state (QuickGO, queried 2026-11-06). GO:0038179 neurotrophin signaling pathway is annotated in D. melanogaster only to Toll-6 (UniProtKB:Q9VUN0), Toll-7 (UniProtKB:Q7KIN0) and kek6 (UniProtKB:A0A0B4KHL5), each by IEA from GO_REF:0000108 (inferred from their GO:0005030 neurotrophin receptor activity, IMP PMID:23892553 for Toll-6 and Toll-7; IDA PMID:28846707 and IBA PTN008615184 for kek6). Neither ligand is on the pathway: NT1 (UniProtKB:B7TB45) and spz5 (UniProtKB:Q9VZX1) carry GO:0008083 and GO:0048018 but their only signaling-pathway process is GO:0008063 Toll signaling pathway (IDA PMID:31088910; spz5 also IDA and IGI PMID:30361090), with neuronal processes GO:0043524 negative regulation of neuron apoptotic process, GO:0008045 motor neuron axon guidance and GO:0031637 regulation of neuronal synaptic plasticity in response to neurotrophin from PMID:19018662. This is the Category B gap of the LIGANDS_IN_SIGNALING check (ligand only on a related pathway term). The fly row for the sibling term GO:0038180 nerve growth factor signaling pathway is Arms (UniProtKB:Q9W2I0, IBA PTN001190877), a propagation from a PAINT node whose fly descendant is the KIDINS220/ARMS orthologue; it is not part of this module. All members have gene reviews (genes/DROME/Toll-7, Toll-6, kek6, NT1, spz5). The NT1 review MODIFIES its Toll signaling pathway row to GO:0038179 and the spz5 review adds GO:0038179 as a NEW row (PMID:23892553), keeping spz5's Toll-1 immune rows as non-core; the Toll-6 review removes the Roundabout-binding IBA from the Slit node and keeps axon guidance on Toll-6's own mutant data. The GOA state described above is unchanged until GO acts on these. module: id: neurotrophin_toll_signaling label: Neurotrophin signaling through Toll-family receptors module_type: SIGNALING_PATHWAY description: >- A secreted Drosophila neurotrophin (DNT1 or DNT2) binds the Toll-family receptors Toll-6 or Toll-7 on a responding neuron, with the kinase-less Trk-like receptor Kek-6 as a DNT2 co-receptor at some synapses, to regulate neuronal survival, axon targeting and synaptic structure. concepts: - preferred_term: neurotrophin signaling pathway term: id: GO:0038179 label: neurotrophin signaling pathway context: taxa: - preferred_term: Drosophila melanogaster term: id: NCBITaxon:7227 label: Drosophila melanogaster parts: - order: 1 role: secreted ligand node: id: dnt_ligand label: Drosophila neurotrophin ligand module_type: SIGNALING_PATHWAY description: A secreted cystine-knot neurotrophin, DNT1 or DNT2, produced by target or intermediate-target tissues such as muscle and the CNS midline. annotons: - id: dnt1_dnt2_ligand_family label: DNT1/DNT2 neurotrophin ligand participant: selector_type: FAMILY family: preferred_term: Drosophila neurotrophins DNT1 and DNT2 (Spaetzle-family cystine-knot ligands) term: id: PANTHER:PTHR23199 label: NEUROTROPHIN 1-RELATED description: >- PTHR23199 also contains Spaetzle (the Toll-1 ligand), Spz3, Spz4, Spz6 and horseshoe-crab coagulogen, which are not neurotrophin ligands of Toll-6/Toll-7. The role is restricted to DNT1 (NT1/Spz2, in PTHR23199:SF12) and DNT2 (Spz5, PTHR23199:SF16), the members shown to bind Toll-6 and Toll-7. representative_members: - preferred_term: NT1 (DNT1) term: id: UniProtKB:B7TB45 label: Neurotrophin 1 - preferred_term: spz5 (DNT2) term: id: UniProtKB:Q9VZX1 label: Protein spaetzle 5 ancestral_nodes: - preferred_term: PAINT node PTN002354018 (Spaetzle-family growth factors) term: id: PANTHER:PTN002354018 label: PTN002354018 description: >- Local PAINT IBD node in PTHR23199 (taxon column empty) with propagated terms C:GO:0005576, F:GO:0005121, F:GO:0008083, P:GO:0021556 and P:GO:0045087. Its GO:0008083 growth factor activity seeds are Drosophila spz (FB:FBgn0003495), spz5 (FB:FBgn0035379) and NT1 (FB:FBgn0261526). The node's F:GO:0008083 matches the step's function; its F:GO:0005121 Toll binding is the receptor-specific binding term the step does not use, and its P:GO:0045087 innate immune response reflects the Spaetzle-Toll-1 immune role rather than neurotrophin signaling. evidence: - source_id: GO_REF:0000033 statement: IBD propagation from PAINT node PTN002354018 in PTHR23199. function: preferred_term: growth factor activity term: id: GO:0008083 label: growth factor activity processes: - preferred_term: neurotrophin signaling pathway term: id: GO:0038179 label: neurotrophin signaling pathway locations: - preferred_term: extracellular region term: id: GO:0005576 label: extracellular region role_description: Secreted neurotrophin that binds Toll-6 and Toll-7 (and, for DNT2, Kek-6) to promote neuronal survival and axon targeting. evidence: - source_id: PMID:19018662 title: Drosophila neurotrophins reveal a common mechanism for nervous system formation. statement: DNT1 is a neurotrophic factor required for neuronal survival and motor axon targeting; DNT2 and Spz also have neurotrophic functions. supporting_text: >- We show that Spätzle and a further fly neurotrophin superfamily member, DNT2, also have neurotrophic functions in flies. - source_id: PMID:19018662 title: Drosophila neurotrophins reveal a common mechanism for nervous system formation. statement: The DNT1 cystine knot is conserved across insects. supporting_text: >- The DNT1 Cysknot is highly conserved in all sequenced insects, such as fruit fly (Drosophila), mosquito (Anopheles), and bee (Apis) - source_id: PMID:23892553 title: Toll-6 and Toll-7 function as neurotrophin receptors in the Drosophila melanogaster CNS. statement: DNT1 binds Toll-7, and DNT2 binds both Toll-6 and Toll-7. supporting_text: >- Together, these data demonstrate that DNT1 binds Toll-7 and DNT2 binds promiscuously Toll-6 and Toll-7. - order: 2 role: receptor node: id: toll_neurotrophin_receptor label: Toll-family neurotrophin receptor module_type: SIGNALING_PATHWAY description: Transmembrane Toll-family receptor with a leucine-rich-repeat ectodomain and a cytoplasmic TIR domain, expressed by CNS neurons, that binds DNT1 or DNT2. annotons: - id: toll6_toll7_neurotrophin_receptor label: Toll-6/Toll-7 neurotrophin receptor participant: selector_type: FAMILY family: preferred_term: Toll-6 and Toll-7 neurotrophin receptors description: >- No PANTHER id is asserted. UniProt places Toll-6 in PTHR24366:SF96 and Toll-7 in PTHR45712:SF22, two different families, and neither is in PTHR24365 (TOLL-LIKE RECEPTOR). No PAINT node is shared by the two receptors. representative_members: - preferred_term: Toll-6 term: id: UniProtKB:Q9VUN0 label: Toll-like receptor 6 - preferred_term: Toll-7 term: id: UniProtKB:Q7KIN0 label: Toll-like receptor 7 function: preferred_term: neurotrophin receptor activity term: id: GO:0005030 label: neurotrophin receptor activity processes: - preferred_term: neurotrophin signaling pathway term: id: GO:0038179 label: neurotrophin signaling pathway locations: - preferred_term: plasma membrane term: id: GO:0005886 label: plasma membrane role_description: Neuronal Toll receptor that binds DNT1 or DNT2 and signals to promote neuronal survival and motor axon targeting, or, through alternative adaptors, neuronal death. evidence: - source_id: PMID:23892553 title: Toll-6 and Toll-7 function as neurotrophin receptors in the Drosophila melanogaster CNS. statement: Toll-6 and Toll-7 are neurotrophin receptors in Drosophila, which lacks Trk, p75NTR and Sortilin receptors. supporting_text: >- Here we show that Toll paralogs unrelated to the mammalian neurotrophin receptors function as neurotrophin receptors in fruit flies. - source_id: PMID:28373203 title: Three-tier regulation of cell number plasticity by neurotrophins and Tolls in Drosophila. statement: Downstream adaptors determine whether Toll-6 signaling promotes survival or death. supporting_text: >- Third, distinct adaptors downstream of Tolls can drive either apoptosis or cell survival. - source_id: file:genes/DROME/Toll-7/Toll-7-ai-review.yaml statement: The Toll-7 gene review gives GO:0005030 neurotrophin receptor activity as its core molecular function, involved in GO:0038179. - order: 3 role: co-receptor optional: true node: id: kek6_coreceptor label: Kekkon-6 Trk-like co-receptor module_type: SIGNALING_PATHWAY description: Kinase-less Trk-like LRR/Ig receptor that binds DNT2 at presynaptic motor neuron terminals and acts together with Toll-6 in structural synaptic plasticity. annotons: - id: kek6_dnt2_receptor label: Kek-6 DNT2 receptor participant: selector_type: FAMILY family: preferred_term: Kekkon-6 term: id: PANTHER:PTHR24366:SF87 label: KEKKON 6, ISOFORM B representative_members: - preferred_term: kek6 term: id: UniProtKB:A0A0B4KHL5 label: Kekkon 6, isoform B ancestral_nodes: - preferred_term: PAINT node PTN008615184 (Kek-6) term: id: PANTHER:PTN008615184 label: PTN008615184 description: >- Local PAINT IBD node in PTHR24366 (taxon column empty) with propagated terms C:GO:0061174, F:GO:0005030 and P:GO:0048167, seeded only by Drosophila kek6 (FB:FBgn0039862). Its F:GO:0005030 matches the step's function. evidence: - source_id: GO_REF:0000033 statement: IBD propagation from PAINT node PTN008615184 in PTHR24366. function: preferred_term: neurotrophin receptor activity term: id: GO:0005030 label: neurotrophin receptor activity processes: - preferred_term: neurotrophin signaling pathway term: id: GO:0038179 label: neurotrophin signaling pathway locations: - preferred_term: type I terminal bouton term: id: GO:0061174 label: type I terminal bouton role_description: DNT2-binding Trk-like receptor that interacts with Toll-6 and, through CaMKII and VAP33A, regulates neuromuscular junction growth. evidence: - source_id: PMID:28846707 title: 'Kek-6: A truncated-Trk-like receptor for Drosophila neurotrophin 2 regulates structural synaptic plasticity.' statement: Kek-6 binds DNT2 (and DNT1) and is a kinase-less Trk-family receptor. supporting_text: >- Kek-6 is expressed in the CNS, interacts genetically with DNTs and can bind DNT2 in signaling assays and co-immunoprecipitations. - source_id: PMID:28846707 title: 'Kek-6: A truncated-Trk-like receptor for Drosophila neurotrophin 2 regulates structural synaptic plasticity.' statement: Kek-6 does not antagonise Toll-6 but acts together with it. supporting_text: >- Evidence indicates that Kek-6 does not antagonise the alternative DNT2 receptor Toll-6. Instead, Kek-6 and Toll-6 interact physically, and together regulate structural synaptic plasticity and homeostasis. - source_id: PMID:39704728 title: A neurotrophin functioning with a Toll regulates structural plasticity in a dopaminergic circuit. statement: DNT-2 acts with Toll-6 and Kek-6 in structural plasticity of a dopaminergic circuit. supporting_text: >- DNT-2 with Toll-6 and Kek-6 induced structural plasticity in this circuit modifying brain function and behaviour. connections: - source: dnt_ligand target: toll_neurotrophin_receptor connection_type: POSITIVELY_REGULATES description: DNT1 or DNT2 binding activates Toll-6 or Toll-7. - source: dnt_ligand target: kek6_coreceptor connection_type: POSITIVELY_REGULATES description: DNT2 binds Kek-6, which acts together with Toll-6 at the synapse. knowledge_gaps: - gap_statement: Whether neurotrophin signaling through Toll receptors is an ancient mechanism shared beyond Drosophila, including whether insect DNT orthologues signal through Toll-6/Toll-7 orthologues and whether the DNT and vertebrate neurotrophin cystine knots are homologous or convergent, is not known. boundary: In D. melanogaster DNT1 and DNT2 bind Toll-6 and Toll-7 and require them for neuronal survival and motor axon targeting; DNT1 and Spz5 sequences are highly conserved across insects. status: OPEN gap_kind: - BIOLOGY significance: The answer sets the taxon scope of this module and decides whether Toll-mediated neurotrophism is an insect innovation or an ancestral bilaterian mechanism. resolution: Test ligand binding and receptor requirement for DNT and Toll-6/Toll-7 orthologues in a second insect order (for example Tribolium) and in a non-insect protostome. provenance: - reference_id: PMID:23892553 supporting_text: >- Or is the relationship uncovered here between the neurotrophin-ligand and Toll-receptor superfamilies an ancient mechanism of nervous system formation? - reference_id: PMID:19018662 supporting_text: >- This could mean that NTs appeared independently in deuterostomes and insects, and their similarity is due to convergence.