{"doi":"10.1242/dev.200748","title":"A metazoan-specific C-terminal motif in EXC-4 and Gα-Rho/Rac signaling regulate cell outgrowth during tubulogenesis in <i>C. elegans</i>","abstract":"Chloride intracellular channels (CLICs) are conserved proteins for which the cellular and molecular functions remain mysterious. An important insight into CLIC function came from the discovery that Caenorhabditis elegans EXC-4/CLIC regulates morphogenesis of the excretory canal (ExCa) cell, a single-cell tube. Subsequent work showed that mammalian CLICs regulate vascular development and angiogenesis, and human CLIC1 can rescue exc-4 mutants, suggesting conserved function in biological tube formation (tubulogenesis) and maintenance. However, the cell behaviors and signaling pathways regulated by EXC-4/CLICs during tubulogenesis in vivo remain largely unknown. We report a new exc-4 mutation, affecting a C-terminal residue conserved in virtually all metazoan CLICs, that reveals a specific role for EXC-4 in ExCa outgrowth. Cell culture studies suggest a function for CLICs in heterotrimeric G protein (Gα/β/γ)-Rho/Rac signaling, and Rho-family GTPases are common regulators of cell outgrowth. Using our new exc-4 mutant, we describe a previously unknown function for Gα-encoding genes (gpa-12/Gα12/13, gpa-7/Gαi, egl-30/Gαq and gsa-1/Gαs), ced-10/Rac and mig-2/RhoG in EXC-4-mediated ExCa outgrowth. Our results demonstrate that EXC-4/CLICs are primordial players in Gα-Rho/Rac-signaling, a pathway that is crucial for tubulogenesis in C. elegans and in vascular development.","journal":"Development","year":2022,"id":285713,"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":5,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9603,"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":964315,"name":"Julianna Escudero","orcid":"0000-0002-7613-7332","position":1,"is_corresponding":false},{"id":718100,"name":"Daniel D. Shaye","orcid":"0000-0002-3962-6903","position":2,"is_corresponding":false},{"id":828341,"name":"Anthony F. Arena","orcid":null,"position":0,"is_corresponding":true}],"reference_count":93,"raw_metadata":null,"created_at":"2026-07-19T00:29:44.944555Z","pmid":"36398726","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":[]}