Toll-6 is a Toll-family type I transmembrane receptor with an extracellular leucine-rich-repeat ectodomain and a cytoplasmic TIR domain, closely related to the long Toll receptors 18w (Toll-2), Toll-7 and Toll-8. It is expressed in the embryonic, larval and adult central nervous system and is a cell-surface receptor for the SpΓ€tzle-family neurotrophins DNT2 (Spz5) and, promiscuously, DNT1 (Spz2). Neurotrophin binding to Toll-6 promotes neuronal survival through MyD88 and NF-kappaB, while in other contexts Toll-6 promotes cell death through Wek, Sarm and JNK; in motoneurons a Toll-6, dSARM and FoxO pathway regulates microtubule dynamics. Together with Toll-7 it is required for motor axon targeting, neuronal survival and locomotion, and with the kinase-less Trk-like receptor Kek-6 it regulates neuromuscular junction growth, active zone formation and structural plasticity of dopaminergic circuits. In the olfactory system Toll-6 acts cell autonomously in projection neurons to instruct dendrite targeting and synaptic partner matching, independently of its cytoplasmic domain. In the early embryo Toll-6 is expressed in stripes and acts with Toll-2 and Toll-8 in a positional code that directs planar polarity, cell intercalation and convergent extension. Spz5 signalling through Toll-6 also primes glia for phagocytosis of dying neurons. Toll-6 is not required for antimicrobial peptide induction.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0003401 axis elongation | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: ARBA machine-learning prediction of a role in axis elongation, matching the experimental IGI row from the positional Toll code study. Reason: Supported by the embryonic convergent-extension work, in which Toll-6 acts redundantly with Toll-2 and Toll-8 in a positional code; this is a developmental role peripheral to the neurotrophin receptor function, so non-core, consistent with the IGI row for the same term. Supporting Evidence: PMID:25363762 These results demonstrate that Toll-2, Toll-6, and Toll-8 act in combination to regulate axis elongation. |
| GO:0003401 axis elongation | IGI PMID:25363762 A positional Toll receptor code directs convergent extension... | KEEP AS NON CORE | Summary: Removing Toll-2, Toll-6 and Toll-8 together reduces germband axis elongation; Toll-6 contributes through a striped, positional receptor code. Reason: Genetic interaction data (double and triple loss of function with Toll-2 and Toll-8) show Toll-6 contributes to axis elongation by directing planar polarity and cell intercalation. The receptors act through heterophilic cell-surface interactions between stripes, so Toll-6 does part of the work of the process. Real but peripheral to the core neurotrophin receptor role. Supporting Evidence: PMID:25363762 These results demonstrate that Toll-2, Toll-6, and Toll-8 act in combination to regulate axis elongation. PMID:25363762 These results indicate that Toll-2 can promote heterophilic interactions with cells expressing Toll-6 or Toll-8. |
| GO:0005030 neurotrophin receptor activity | IMP PMID:23892553 Toll-6 and Toll-7 function as neurotrophin receptors in the ... | ACCEPT | Summary: Toll-6 is a receptor for the Drosophila neurotrophins DNT2 (Spz5) and DNT1 (Spz2). Reason: Genetic interaction with DNT2/DNT1 mutants, rescue of DNT mutant cell death by activated Toll-6, binding of DNT2 to the Toll-6 ectodomain and DNT2-induced NF-kappaB signalling in Toll-6-expressing cells together establish Toll-6 as a neurotrophin receptor. Core molecular function, as for its paralog Toll-7. Supporting Evidence: PMID:23892553 Here we show that Toll paralogs unrelated to the mammalian neurotrophin receptors function as neurotrophin receptors in fruit flies. PMID:23892553 This indicates that DNT2 interacts with both Toll-6 and Toll-7. PMID:28373203 This shows that Toll-6 and -7 activate NF-ΞΊB signaling downstream of DNT2. |
| GO:0005886 plasma membrane | IEA GO_REF:0000044 | ACCEPT | Summary: UniProt subcellular-location mapping to plasma membrane. Reason: Toll-6 is a single-pass type I membrane receptor with a signal peptide and one transmembrane segment, and is reported at the membrane in neurons; it binds secreted DNT2 through its ectodomain, so the plasma membrane is where the receptor function acts. Supporting Evidence: PMID:23892553 In Toll-6MIMICGFP, GFP is mostly cytoplasmic whereas Toll-6 is localised to the membrane file:DROME/Toll-6/Toll-6-uniprot.txt FT TRANSMEM 1058..1078 |
| GO:0007165 signal transduction | IEA GO_REF:0000120 | MODIFY | Summary: Combined IEA from the TIR domain and an ARBA rule. Reason: Correct but general. Toll-6 transduces signals from the neurotrophins DNT1 and DNT2 (Spz5), so the specific supported process is neurotrophin signaling pathway (GO:0038179), which the gene already carries. Proposed replacements: neurotrophin signaling pathway Supporting Evidence: PMID:28373203 Collectively, these data show that Toll-6 and -7 signal via the canonical MyD88 pathway to promote neuronal survival in the CNS. |
| GO:0007165 signal transduction | IMP PMID:31088910 Toll family members bind multiple SpΓ€tzle proteins and activ... | MODIFY | Summary: Signal transduction by Toll-6 attributed to Chowdhury et al. 2019, a study of SpΓ€tzle binding to Toll-1 and Toll-7. Reason: In the cached full text of PMID:31088910, Toll-6 appears only in citations of McIlroy et al. 2013 and of an earlier Toll-1/TIR chimera study; I could not find the Toll-6 loss-of-function data behind this IMP (it may be in supplementary material not cached), so I defer to the curator on the evidence. The claim itself is true and independently well established (PMID:28373203), but general; as for the IEA row on this term, the specific supported process is neurotrophin signaling pathway (GO:0038179), which the gene already carries. 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:28373203 This shows that Toll-6 and -7 activate NF-ΞΊB signaling downstream of DNT2. |
| GO:0007411 axon guidance | IBA GO_REF:0000033 | ACCEPT | Summary: IBA from the PTHR45836 (SLIT HOMOLOG) family-root node PTN002911625, seeded by Slit guidance ligands; Toll-6 receives it because the PANTHER tree places it in subfamily SF8 of the Slit family. Reason: The ancestral source is wrong for this gene: the node asserts the Slit-Robo repulsive guidance-cue role, and Toll-6 is a Toll-family LRR/TIR receptor whose placement in the Slit clade conflicts with its domain architecture and with UniProt's HMM classification (PTHR24366:SF96). The claim itself is nevertheless true of Toll-6 on independent experimental evidence: Toll-6 null mutants show motor axon misrouting, and Toll-6 in projection neurons is required for VA1d olfactory receptor neuron axon targeting. The term is kept on that evidence, as for the paralog Toll-7, not on the Slit inheritance. Propagation Review Root cause: PROPAGATION BAD Failure modes: WRONG ORTHOLOG OR PARALOG ROLE CONFLATION Sources checked: PANTHER:PTN002911625 SUPPORTS SOURCE BUT NOT TARGET Family root of the Slit/Notch tree seeded by Slit ligands and a Nogo receptor; Toll-6 sits in it only by an LRR-driven tree placement. The term holds for Toll-6 on its own mutant data, not by descent from Slit. Supporting Evidence: PMID:23892553 Altogether, our data show that Toll-6 and Toll-7 are required for locomotion, motor-axon targeting and neuronal survival. PMID:25741726 toll-6 mutants exhibited dorsal mistargeting of VA1d ORN axons |
| GO:0008201 heparin binding | IBA GO_REF:0000033 | MARK AS OVER ANNOTATED | Summary: IBA from Slit-clade node PTN002911633, seeded by Slit proteins and Nogo receptors. Reason: Toll-6 inherits this only because the PANTHER tree places it (subfamily SF8) inside the Slit clade of PTHR45836, while its domain architecture (LRR ectodomain, transmembrane segment, cytoplasmic TIR domain) and UniProt's HMM assignment (PTHR24366:SF96) mark it as a Toll-like receptor whose closest paralogs are 18w, Toll-7 and Toll-8. No study has tested heparin binding by Toll-6. LRR ectodomains can bind glycosaminoglycans, so the claim is not demonstrably wrong, but it rests only on a doubtful tree placement and is not part of the known biology of the receptor. Propagation Review Root cause: PROPAGATION BAD Failure modes: WRONG ORTHOLOG OR PARALOG Sources checked: PANTHER:PTN002911633 SUPPORTS SOURCE BUT NOT TARGET Bilaterian Slit/Nogo-receptor node; heparin binding is shown for the seeds, untested for the Toll-6 branch, which is in the clade only by tree placement. Supporting Evidence: file:DROME/Toll-6/Toll-6-uniprot.txt Belongs to the Toll-like receptor family. file:DROME/Toll-6/Toll-6-uniprot.txt DR PANTHER; PTHR24366:SF96; LEUCINE RICH REPEAT CONTAINING 53; 1. PMID:21158756 Overexpression of Toll and Toll-9 suggested their functional similarities, while 18w, Toll-6, Toll-7 and Toll-8 often showed related phenotypes. |
| GO:0038179 neurotrophin signaling pathway | IEA GO_REF:0000108 | ACCEPT | Summary: Inferred from neurotrophin receptor activity. Reason: Toll-6 is the receptor that initiates DNT2/DNT1 signalling, promoting neuronal survival via MyD88 and NF-kappaB; core process. Supporting Evidence: PMID:28373203 Collectively, these data show that Toll-6 and -7 signal via the canonical MyD88 pathway to promote neuronal survival in the CNS. PMID:23892553 Here we show that Toll paralogs unrelated to the mammalian neurotrophin receptors function as neurotrophin receptors in fruit flies. |
| GO:0048167 regulation of synaptic plasticity | IGI PMID:28846707 Kek-6: A truncated-Trk-like receptor for Drosophila neurotro... | ACCEPT | Summary: Toll-6 acts with DNT2 and Kek-6 to regulate NMJ growth, active zone formation and structural synaptic homeostasis. Reason: Toll-6 mutants have smaller NMJs and fewer active zones, and kek-6 Toll-6 double mutants fail to show homeostatic compensation of active zones. Independent work shows Toll-6 and Kek-6 are required for structural plasticity of a dopaminergic circuit in the adult brain and that Toll-6-dSARM-FoxO signalling is needed for activity-dependent structural plasticity of motoneurons. Structural synaptic plasticity downstream of neurotrophin signalling is a core role. Supporting Evidence: PMID:28846707 Kek-6 and Toll-6 interact physically, and together regulate structural synaptic plasticity and homeostasis. PMID:28846707 Toll-6 is required for active zone formation PMID:39704728 DNT-2 with Toll-6 and Kek-6 induced structural plasticity in this circuit modifying brain function and behaviour. PMID:27502486 it is essential for axon transport and structural plasticity in motoneurons |
| GO:0048495 Roundabout binding | IBA GO_REF:0000033 | REMOVE | Summary: IBA from Slit-clade node PTN002911633, seeded only by Slit ligands (human SLIT1-3, Drosophila Slit). Reason: Robo binding is the defining ligand property of Slit proteins, carried by their second LRR domain within a Slit-specific architecture (four LRR domains, EGF repeats, laminin-G and C-terminal cystine-knot domains). Toll-6 lacks that architecture; it is a Toll-like receptor (LRR ectodomain, transmembrane segment, TIR domain) whose ligands are the SpΓ€tzle-family neurotrophins, and no study reports Toll-6 binding Robo. Its inclusion in the Slit clade (PANTHER subfamily PTHR45836:SF8) is contradicted by UniProt's HMM assignment to PTHR24366:SF96 and by its clear paralogy to 18w, Toll-7 and Toll-8. The family review for PTHR45836 already records PTN002911633 as NEEDS_PRUNING for SF8. This is an over-propagated IBA argued against on biological grounds. Propagation Review Root cause: PROPAGATION BAD Failure modes: WRONG ORTHOLOG OR PARALOG ROLE CONFLATION Sources checked: PANTHER:PTN002911633 SUPPORTS SOURCE BUT NOT TARGET Robo binding is sound for the Slit seeds; the Toll-6 (SF8) branch should be pruned with an IRD, as recorded in the PTHR45836 family review. Supporting Evidence: file:DROME/Toll-6/Toll-6-uniprot.txt Belongs to the Toll-like receptor family. file:DROME/Toll-6/Toll-6-uniprot.txt DR PANTHER; PTHR24366:SF96; LEUCINE RICH REPEAT CONTAINING 53; 1. PMID:23892553 This indicates that DNT2 interacts with both Toll-6 and Toll-7. |
| GO:0048666 neuron development | IEA GO_REF:0000117 | MODIFY | Summary: ARBA prediction of a role in neuron development. Reason: Correct but general. The neuronal developmental roles of Toll-6 shown experimentally are projection-neuron dendrite targeting and motor/olfactory axon targeting, both already carried by the gene (dendrite guidance GO:0070983, axon guidance GO:0007411). Proposed replacements: dendrite guidance axon guidance Supporting Evidence: PMID:25741726 Toll-6 and Toll-7, members of the Toll receptor family best known for functions in innate immunity and embryonic patterning, cell autonomously instruct the targeting of specific classes of PN dendrites and ORN axons, respectively PMID:23892553 Altogether, our data show that Toll-6 and Toll-7 are required for locomotion, motor-axon targeting and neuronal survival. |
| GO:0060026 convergent extension | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: ARBA prediction matching the experimental IGI row. Reason: Supported by the positional Toll code study; developmental role, non-core, as for the IGI row. Supporting Evidence: PMID:25363762 These results demonstrate that Toll-2, Toll-6, and Toll-8 promote cell intercalation during axis elongation. |
| GO:0060026 convergent extension | IGI PMID:25363762 A positional Toll receptor code directs convergent extension... | KEEP AS NON CORE | Summary: Toll-6, with Toll-2 and Toll-8, is required for cell intercalation and myosin II/Par-3 planar polarity during germband extension. Reason: Combined loss of Toll-2, Toll-6 and Toll-8 impairs planar polarity, cell intercalation and convergent extension. Genuine, but peripheral to the neurotrophin receptor function and partly redundant. Supporting Evidence: PMID:25363762 These results demonstrate that Toll-2, Toll-6, and Toll-8 promote cell intercalation during axis elongation. PMID:25363762 These results demonstrate that Toll-2, Toll-6 and Toll-8 act together to regulate myosin II and Par-3 planar polarity. |
| GO:0070983 dendrite guidance | IMP PMID:25741726 Toll receptors instruct axon and dendrite targeting and part... | ACCEPT | Summary: Toll-6 acts cell autonomously in olfactory projection neurons to instruct dendrite targeting to specific glomeruli. Reason: MARCM loss-of-function clones show cell-autonomous dendrite mistargeting of VA1d/DC3 projection neurons; core neuronal wiring role, mediated by the ectodomain (the cytoplasmic domain is dispensable). Supporting Evidence: PMID:25741726 Toll-6 and Toll-7, members of the Toll receptor family best known for functions in innate immunity and embryonic patterning, cell autonomously instruct the targeting of specific classes of PN dendrites and ORN axons, respectively PMID:25741726 Lastly, we found the cytoplasmic domains of Toll-6 and Toll-7 to be dispensable for their activities in PNs and ORNs, respectively |
| GO:0043524 negative regulation of neuron apoptotic process | IMP PMID:23892553 Toll-6 and Toll-7 function as neurotrophin receptors in the ... | NEW | Summary: Toll-6 is required for, and sufficient to promote, survival of CNS neurons. Reason: Toll-6 mutant embryos have increased CNS apoptosis and lose Eve+ neurons, and activated Toll-6 expressed in neurons rescues naturally occurring cell death and the cell death caused by loss of DNT2. Toll-6 does part of the work as the receptor that initiates the MyD88/NF-kappaB pro-survival signal. This is the principal neurotrophic outcome of the receptor and is not captured by the existing annotations. Toll-6 can also promote apoptosis in other contexts (pupae, via Wek/Sarm/JNK), which the negative-regulation term does not deny; survival is the best-supported in vivo role. Supporting Evidence: PMID:23892553 Altogether, our data show that Toll-6 and Toll-7 are required for locomotion, motor-axon targeting and neuronal survival. PMID:28373203 Collectively, these data show that Toll-6 and -7 signal via the canonical MyD88 pathway to promote neuronal survival in the CNS. |
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Download this section (compressed HTML)Q: Should PAINT add an IRD at the Toll-6 branch (PANTHER PTHR45836:SF8) below the Slit nodes PTN002911633 and PTN002911625, or should Toll-6 be moved out of the SLIT HOMOLOG family to sit with its Toll paralogs (18w, Toll-7, Toll-8) as UniProt's HMM assignment (PTHR24366:SF96) implies?
Q: What ectodomain ligand or co-receptor mediates the cytoplasmic-domain-independent role of Toll-6 in projection-neuron dendrite targeting, and is it DNT2?
Q: Is GO:0005030 neurotrophin receptor activity the right MF for the cytoplasmic-domain-independent wiring role, or does that role need a distinct cell-surface recognition term?
Experiment: Test whether DNT2 (spz5) or DNT1 mutants phenocopy toll-6 VA1d projection-neuron dendrite mistargeting, and whether an ectodomain point mutant that abolishes DNT2 binding still rescues targeting.
Experiment: Measure direct binding of the Toll-6 ectodomain to heparin and to Robo ectodomains (SPR/BLI) to settle the Slit-node IBA claims experimentally.
Toll-6 (Toll-6) encodes a member of the Toll-like receptor family. It has neurotrophin receptor activity and contributes to dendrite guidance. Genetic interaction with 18w and Tollo suggests a Toll-6 role in convergent extension during early embryogenesis.
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