The E3 ubiquitin ligase RNF216/TRIAD3 is a central regulator of the hypothalamic-pituitary-gonadal axis
| Autor: | C. Ware, Ning Fang, Arlene J. George, Yarely C. Hoffiz, Bin Dong, E. Hrabovszky, Angela M. Mabb |
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| Rok vydání: | 2021 |
| Předmět: |
Nervous system
Estrous cycle medicine.medical_specialty medicine.drug_class Hypothalamic–pituitary–gonadal axis Biology medicine.disease Phenotype Ubiquitin ligase medicine.anatomical_structure Endocrinology Hypogonadotropic hypogonadism Internal medicine medicine biology.protein Gonadotropin Immortalised cell line |
| Popis: | SummaryRNF216/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.HighlightsRnf216/Triad3 controls Gnrh and intrinsic hypothalamic cell activityRnf216/Triad3 knockout male mice have greater reproductive impairments than femalesRnf216/Triad3 controls the HPG axis at multiple levels |
| Databáze: | OpenAIRE |
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