18 wheeler (18w, also called Toll-2) is a Toll-family type I transmembrane receptor with an extracellular leucine-rich-repeat ectodomain and a cytoplasmic TIR domain. No ligand has been confirmed biochemically; it is not activated by Spätzle-1, and genetic evidence implicates the neurotrophin DNT-2 (Spätzle-5) in visual-system development. 18W is expressed in segmental stripes in the embryo, in migrating cells and in subsets of ovarian follicle cells, and promotes cell aggregation when expressed in S2 cells. Together with Toll-6 and Toll-8, expressed in overlapping transverse stripes under pair-rule control, it forms a positional cell-surface code that directs planar polarity of myosin II and Par-3, cell intercalation and germband convergent extension. 18w is also required for imaginal disc eversion and adult appendage morphogenesis, follicle cell migration and egg shape, and larval fat body development. It is not required for adult antimicrobial responses and does not act as a pattern recognition receptor for bacteria.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0003401 axis elongation | IGI PMID:25363762 A positional Toll receptor code directs convergent extension... | ACCEPT | Summary: Toll-2 (18w), Toll-6 and Toll-8 act together to drive germband axis elongation. Reason: Direct genetic evidence (triple loss of function) that the three receptors provide positional cues for axis elongation. Supporting Evidence: PMID:25363762 three Toll family receptors, Toll-2, Toll-6 and Toll-8, are expressed in overlapping transverse stripes along the anterior-posterior axis and act in combination to direct planar polarity and polarized cell rearrangements during convergent extension PMID:25363762 Simultaneous disruption of all three receptors strongly reduces actomyosin-driven junctional remodelling and axis elongation |
| GO:0004888 transmembrane signaling receptor activity | ISS PMID:7600965 The Drosophila 18 wheeler is required for morphogenesis and ... | ACCEPT | Summary: Transmembrane signaling receptor activity by similarity to Toll. Reason: 18W has the LRR-TM-TIR architecture of Toll and its TIR domain can signal; no ligand has been identified and Spätzle-1 does not activate it, so the generic receptor term (not cytokine receptor activity) is the appropriate level. Supporting Evidence: PMID:7600965 18w encodes a transmembrane protein with an extracellular moiety containing many leucine rich repeats and cysteine motifs, and an intracellular domain bearing homology to the cytoplasmic portion of the interleukin-1-receptor PMID:31088910 cells co-expressing Toll-2 and the cystine knot for Spz-1 also resulted in either little (3.5–14-fold) or no activation of the drosomycin promoter |
| GO:0005886 plasma membrane | IBA GO_REF:0000033 | ACCEPT | Summary: Plasma membrane localisation of the 18W transmembrane receptor. Reason: Consistent with its type I transmembrane architecture and with cell-surface adhesion activity. Supporting Evidence: PMID:7600965 18w encodes a transmembrane protein with an extracellular moiety containing many leucine rich repeats and cysteine motifs, and an intracellular domain bearing homology to the cytoplasmic portion of the interleukin-1-receptor |
| GO:0005886 plasma membrane | IDA PMID:9321392 The 18-wheeler mutation reveals complex antibacterial gene r... | ACCEPT | Summary: Plasma membrane localisation of the 18W transmembrane receptor. Reason: Consistent with sequence and adhesion data; cached record is abstract-only, deferring to the curator on the assay. Supporting Evidence: PMID:7600965 18w encodes a transmembrane protein with an extracellular moiety containing many leucine rich repeats and cysteine motifs, and an intracellular domain bearing homology to the cytoplasmic portion of the interleukin-1-receptor |
| GO:0005886 plasma membrane | IEA GO_REF:0000120 | ACCEPT | Summary: Plasma membrane localisation of the 18W transmembrane receptor. Reason: Consistent with experimental data. Supporting Evidence: PMID:7600965 18w encodes a transmembrane protein with an extracellular moiety containing many leucine rich repeats and cysteine motifs, and an intracellular domain bearing homology to the cytoplasmic portion of the interleukin-1-receptor |
| GO:0005886 plasma membrane | ISS PMID:7600965 The Drosophila 18 wheeler is required for morphogenesis and ... | ACCEPT | Summary: Plasma membrane localisation of the 18W transmembrane receptor. Reason: Consistent with experimental data. Supporting Evidence: PMID:7600965 18w encodes a transmembrane protein with an extracellular moiety containing many leucine rich repeats and cysteine motifs, and an intracellular domain bearing homology to the cytoplasmic portion of the interleukin-1-receptor |
| GO:0006955 immune response | IEP PMID:9321392 The 18-wheeler mutation reveals complex antibacterial gene r... | MARK AS OVER ANNOTATED | Summary: 18w expression is induced after infection. Reason: Expression induction alone does not show participation in immune responses, and later genetic analysis found 18w dispensable for adult immune responses and its larval effect secondary to fat-body developmental delay. Supporting Evidence: PMID:9321392 Finally, 18-wheeler (18w) expression is induced in response PMID:12101100 Here we re-examine the role of 18-Wheeler and show that in adults it is dispensable for immune responses. PMID:12101100 In larvae, 18wheeler is required for normal fat body development, and in mutant larvae induction of all antimicrobial peptide genes, and not only of those directed against Gram-negative bacteria, is compromised. |
| GO:0007155 cell adhesion | IDA PMID:7600965 The Drosophila 18 wheeler is required for morphogenesis and ... | ACCEPT | Summary: Expression of 18W in S2 cells induces cell aggregation. Reason: Adhesive, cell-surface interaction activity is consistent with its role as a positional cue in convergent extension (where Toll-2-expressing cells also aggregate with other cells). Supporting Evidence: PMID:7600965 Expression of 18W protein in non-adhesive Schneider 2 cells promotes rapid and robust aggregation of cells. |
| GO:0007165 signal transduction | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic inference of signal transduction for a TIR-domain receptor. Reason: General and correct: the 18W TIR domain can signal when overexpressed, and 18w acts in cell-surface signalling during morphogenesis. Supporting Evidence: PMID:31088910 each TIR significantly activated the drosomycin reporter (7–54-fold) above an empty plasmid/pGL3B control |
| GO:0007165 signal transduction | IEA GO_REF:0000120 | ACCEPT | Summary: Signal transduction from TIR domain (InterPro IPR000157). Reason: General and correct. Supporting Evidence: PMID:7600965 18w encodes a transmembrane protein with an extracellular moiety containing many leucine rich repeats and cysteine motifs, and an intracellular domain bearing homology to the cytoplasmic portion of the interleukin-1-receptor |
| GO:0007165 signal transduction | IMP PMID:31088910 Toll family members bind multiple Spätzle proteins and activ... | ACCEPT | Summary: The isolated 18W (Toll-2) TIR domain activated a drosomycin reporter in S2 cells. Reason: Supports a generic signalling capacity of the TIR domain. The same study found that Spätzle-1 does not activate Toll-2, and an earlier chimera study found no drosomycin induction by the 18W cytoplasmic domain, so this should not be read as Toll-pathway or immune signalling. Supporting Evidence: PMID:31088910 each TIR significantly activated the drosomycin reporter (7–54-fold) above an empty plasmid/pGL3B control PMID:31088910 cells co-expressing Toll-2 and the cystine knot for Spz-1 also resulted in either little (3.5–14-fold) or no activation of the drosomycin promoter PMID:10973475 neither the 18W nor the Toll-6 to Toll-8 chimerae were able to induce drosomycin |
| GO:0007297 follicle cell of egg chamber migration | IMP PMID:16607637 Expression of 18-wheeler in the follicle cell epithelium aff... | KEEP AS NON CORE | Summary: 18w mutant follicle cell clones show delayed follicle cell migrations. Reason: Developmental role in oogenesis; non-core. Supporting Evidence: PMID:16607637 Females carrying loss-of-function 18w mutant clones in their ovaries show delayed follicle cell migrations. |
| GO:0007419 ventral cord development | HMP PMID:26092715 Novel Genes Involved in Controlling Specification of Drosoph... | KEEP AS NON CORE | Summary: An 18w allele from a forward screen affects specification of Ap4/FMRFa neurons in the ventral nerve cord. Reason: Screen-level evidence for a CNS developmental role; retained as non-core. Supporting Evidence: PMID:26092715 The 18w allele that we isolated displayed loss of Ap cell |
| GO:0009653 anatomical structure morphogenesis | IEA GO_REF:0000117 | ACCEPT | Summary: ARBA-predicted role in anatomical structure morphogenesis. Reason: Consistent with experimental data (IMP from PMID:7600965). Supporting Evidence: PMID:7600965 Escaping mutant adults often display leg, antenna, and wing deformities, presumably resulting from improper eversion of imaginal discs. |
| GO:0009653 anatomical structure morphogenesis | IMP PMID:7600965 The Drosophila 18 wheeler is required for morphogenesis and ... | ACCEPT | Summary: 18w mutants die as larvae or have leg, antenna and wing deformities from defective imaginal disc eversion. Reason: Core developmental role of 18w. Supporting Evidence: PMID:7600965 Escaping mutant adults often display leg, antenna, and wing deformities, presumably resulting from improper eversion of imaginal discs. |
| GO:0019730 antimicrobial humoral response | IMP NOT PMID:12101100 Critical evaluation of the role of the Toll-like receptor 18... | ACCEPT | Summary: NOT annotation: 18w is dispensable for the antimicrobial humoral response in adults. Reason: The NOT statement is directly supported: adult 18w mutants mount normal antimicrobial peptide responses and 18W is not a pattern recognition receptor for Gram-negative bacteria. Supporting Evidence: PMID:12101100 Here we re-examine the role of 18-Wheeler and show that in adults it is dispensable for immune responses. PMID:12101100 18-Wheeler does not qualify as a pattern recognition receptor of Gram-negative bacteria. |
| GO:0019731 antibacterial humoral response | IMP PMID:9321392 The 18-wheeler mutation reveals complex antibacterial gene r... | MARK AS OVER ANNOTATED | Summary: 18w mutant larvae show reduced antibacterial peptide induction and increased susceptibility to bacterial infection. Reason: The larval phenotype was re-examined: induction of all AMP genes (not only antibacterial ones) is reduced because fat body development is delayed, and adults are unaffected. The immune defect is therefore indirect; 18w is not an immune receptor. Supporting Evidence: PMID:9321392 In the absence of the 18W receptor, larvae are more susceptible to bacterial infection. PMID:12101100 In larvae, 18wheeler is required for normal fat body development, and in mutant larvae induction of all antimicrobial peptide genes, and not only of those directed against Gram-negative bacteria, is compromised. PMID:12101100 the data point to a general developmental delay of the fat body as a result of the mutation file:DROME/18w/18w-deep-research-falcon.md The immune phenotype is therefore best interpreted as secondary to defective tissue development rather than direct microbial recognition. |
| GO:0030703 eggshell formation | IMP PMID:16607637 Expression of 18-wheeler in the follicle cell epithelium aff... | KEEP AS NON CORE | Summary: Eggs laid by females with 18w mutant follicle-cell clones have abnormal morphology. Reason: Consequence of follicle cell migration defects; non-core. Supporting Evidence: PMID:16607637 Females carrying loss-of-function 18w mutant clones in their ovaries show delayed follicle cell migrations. |
| GO:0048666 neuron development | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: ARBA-predicted role in neuron development. Reason: Weakly supported for 18w by a single screen hit affecting Ap4/FMRFa neuron specification; non-core. Supporting Evidence: PMID:26092715 The 18w allele that we isolated displayed loss of Ap cell |
| GO:0060026 convergent extension | IGI PMID:25363762 A positional Toll receptor code directs convergent extension... | ACCEPT | Summary: Toll-2 (18w), Toll-6 and Toll-8 form a positional code directing planar polarity and cell intercalation during convergent extension. Reason: Best-characterised function of 18w; a core developmental role. Supporting Evidence: PMID:25363762 three Toll family receptors, Toll-2, Toll-6 and Toll-8, are expressed in overlapping transverse stripes along the anterior-posterior axis and act in combination to direct planar polarity and polarized cell rearrangements during convergent extension |
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Download this section (compressed HTML)Q: What is the ligand (if any) of 18W/Toll-2 in convergent extension: heterophilic binding to Toll-6/Toll-8 or other cell-surface proteins, or a Spätzle-family cytokine other than Spz-1?
Q: Does 18W signal through its TIR domain (MyD88/Tube/Pelle) during convergent extension, or does it act mainly as an adhesion/recognition molecule upstream of myosin II polarity?
Q: Is the larval fat-body phenotype of 18w a direct requirement of 18W or a neomorphic effect of the 18w7-35 allele, as Ligoxygakis et al. raised?
Experiment: Test binding of 18W ectodomain to Toll-6, Toll-8 and Spätzle-family cystine knots with purified proteins, and assay convergent extension with TIR-deleted 18W rescue constructs.
Experiment: Re-examine larval AMP induction and fat-body development with a clean 18w null (CRISPR) allele to separate direct from neomorphic effects.
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Download this section (compressed HTML)18 wheeler (18w) encodes a member of the Toll-like receptor family. It contributes to multiple processes including ovarian follicle cell migration, antibacterial humoral response and ventral cord development. A role in convergent extension during early embryogenesis is suggested by the genetic interaction of 18w with Toll-6 and Tollo.
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