{"doi":"10.1101/2022.06.16.496459","title":"TOM-1/Tomosyn acts with the UNC-6/Netrin receptor UNC-5 to inhibit growth cone protrusion in <i>Caenorhabditis elegans</i>","abstract":"Abstract In the polarity/protrusion model of growth cone repulsion from UNC-6/Netrin, UNC-6 first polarizes the VD growth cone via the UNC-5 receptor, and then regulates protrusion asymmetrically across the growth cone based on this polarity. Through the UNC-40/DCC receptor, UNC-6 stimulates protrusion dorsally, and through UNC-5 inhibits protrusion ventrally and laterally, resulting in net dorsal growth. Previous studies showed that UNC-5 inhibits growth cone protrusion via the flavin monooxygenases and potential destabilization of F-actin, and via UNC-33/CRMP and restriction of microtubule + end entry into the growth cone. To explore the role of vesicle fusion in growth cone protrusion, we analyzed tom-1/tomosyn mutants. Tomosyn normally occludes formation of the SNARE complex by interacting with and inhibiting Syntaxin and thus preventing vesicle fusion. VD growth cones of tom-1 null mutants were similar to wild-type. However, tom-1 null mutants suppressed the effects of constitutively-activated MYR::UNC-5, which alone causes small growth cones with little protrusion. This suggests that TOM-1 is normally required for the inhibitory effects of MYR::UNC-5 on growth cone protrusion. tom-1 encodes long and short isoforms, and results here indicate that tom-1S is required downstream of UNC-5 to inhibit protrusion, whereas the tom-1L has a pro-protrusive role. unc-64/Syntaxin mutants displayed reduced growth cone protrusion, suggesting that TOM-1 inhibits growth cone protrusion by inhibiting UNC-64/Syntaxin, similar to its role in neurotransmission. TOM-1L, TOM-1S, and UNC-64/Syntaxin were all required for VD growth cone polarity of protrusion, indicating that regulated vesicle fusion is required for the establishment and/or maintenance of VD growth cone polarity. These studies show that, in addition to effects on actin and microtubules, UNC-5 might inhibit VD growth cone protrusion by inhibiting growth cone vesicle fusion and thus the ability of growth cones to add plasma membrane necessary for protrusive growth.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2022,"id":309328,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9601,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2022-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":579737,"name":"Erik A. Lundquist","orcid":"0000-0001-6819-4815","position":1,"is_corresponding":false},{"id":829317,"name":"Snehal Mahadik","orcid":"0000-0002-3840-695X","position":0,"is_corresponding":true}],"reference_count":61,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T00:33:11.579763Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}