{"doi":"10.1101/2025.08.22.671798","title":"<i>Caenorhabditis elegans</i> Uses Canonical and Non-canonical Hippo signaling","abstract":"ABSTRACT Hippo signaling is a conserved regulator of tissue homeostasis across metazoans. The Ste20 family kinase Hippo/MST activates the NDR family kinase Warts/LATS to inhibit the transcriptional coactivator Yorkie/YAP/TAZ and its transcription factor partner Scalloped/TEAD. In Caenorhabditis elegans , cell lineages and organ sizes are largely invariant, and classical Hippo phenotypes such as tissue overgrowth are absent. Nevertheless, WTS-1, YAP-1, and the TEAD-like transcription factor EGL-44 form a conserved core module required for larval development past the L2 stage. Crucially, a direct role for Hippo signaling remains unestablished. To address this question, we generated a fluorescently tagged endogenous YAP-1 as a live biomarker of pathway activity. Upon WTS-1 loss, endogenous YAP-1 translocated from cytosol to nucleus in epithelium and intestine. Tissue-specific depletion revealed that intestinal, but not epithelial, WTS-1 is essential for progression past L2. The duplicated Hippo-related kinases CST-1 and CST-2 repressed YAP-1 nuclear localization in the epithelium but not intestine, indicating that intestinal WTS-1 functions without CST-1/2. The Ste20 kinase MIG-15, orthologous to Drosophila Misshapen and mammalian MAP4K4/6/7/8, was redundant with CST-1/2 for larval progression. Yet deficient MIG-15 uniquely increased YAP-1 abundance without driving nuclear localization. By contrast, the Ste20 kinase GCK-2, orthologous to Drosophila Happyhour and mammalian MAP4K1/2/3/5, had no detectable role. Our findings establish C. elegans as a model for Hippo signaling, with a canonical cascade active in the epithelium and noncanonical inputs controlling WTS-1 in the intestine. In this context, YAP-1/EGL-44 outputs are repurposed from growth control to non-proliferative developmental functions.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2025,"id":573465,"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":0.9476,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1266814,"name":"Razan Fakieh","orcid":"0000-0002-3511-2665","position":1,"is_corresponding":false},{"id":1480675,"name":"C’Brionne Hendrix","orcid":null,"position":2,"is_corresponding":false},{"id":397258,"name":"Reid T. Powell","orcid":"0000-0002-6242-8315","position":3,"is_corresponding":false},{"id":475290,"name":"David J. Reiner","orcid":"0000-0002-0344-7161","position":4,"is_corresponding":false},{"id":1006915,"name":"Linh Huynh","orcid":"0000-0003-0540-6811","position":0,"is_corresponding":true}],"reference_count":63,"raw_metadata":null,"created_at":"2026-07-19T02:57:32.445190Z","pmid":"40909657","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":[]}