{"doi":"10.1101/2021.03.21.436306","title":"The E3 ubiquitin ligase RNF216/TRIAD3 is a central regulator of the hypothalamic-pituitary-gonadal axis","abstract":"Summary RNF216/TRIAD3 is an E3 ligase that ubiquitinates substrates in the nervous system. Recessive mutations in RNF216/TRIAD3 cause Gordon Holmes syndrome (GHS), where hypogonadotropic hypogonadism is a core phenotype. However, the functions of RNF216/TRIAD3 within the neuroendocrine system are not well-understood. Here, we used the CRISPR-Cas9 system to knock out Rnf216/Triad3 in GT1-7 cells, a GnRH immortalized cell line derived from mouse hypothalamus. Rnf216/Triad3 knockout cells had decreased steady state Gnrh and reduced calcium transient frequency. To address functions of RNF216/TRIAD3 in vivo , we generated a Rnf216/Triad3 constitutive knockout (KO) mouse. KO mice of both sexes showed reductions in GnRH and soma size. Furthermore, KO mice exhibited sex-specific phenotypes with males showing gonadal impairment and derangements in gonadotropin release compared to KO females, which only had irregular estrous cyclicity. Our work shows that dysfunction of RNF216/TRIAD3 affects the HPG axis in a sex-dependent manner, implicating sex-specific therapeutic interventions for GHS. Highlights Rnf216/Triad3 controls Gnrh and intrinsic hypothalamic cell activity Rnf216/Triad3 knockout male mice have greater reproductive impairments than females Rnf216/Triad3 controls the HPG axis at multiple levels","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2021,"id":223525,"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":0.9576,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":824980,"name":"Yarely C. Hoffiz","orcid":"0000-0003-4269-3725","position":1,"is_corresponding":false},{"id":780072,"name":"Christopher Ware","orcid":"0000-0002-7459-2358","position":2,"is_corresponding":false},{"id":824981,"name":"Bin Dong","orcid":"0000-0002-0349-446X","position":3,"is_corresponding":false},{"id":446076,"name":"Ning Fang","orcid":"0000-0003-4710-0984","position":4,"is_corresponding":false},{"id":824982,"name":"Erik Hrabovszky","orcid":"0000-0001-6927-0015","position":5,"is_corresponding":false},{"id":337825,"name":"Angela M. Mabb","orcid":"0000-0002-3000-8690","position":6,"is_corresponding":false},{"id":824979,"name":"Arlene J. George","orcid":"0000-0003-0844-088X","position":0,"is_corresponding":true}],"reference_count":93,"raw_metadata":null,"created_at":"2026-07-18T23:54:11.061295Z","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":[]}