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bioRxiv · 10.1101/2021.03.21.436306

The E3 ubiquitin ligase RNF216/TRIAD3 is a central regulator of the hypothalamic-pituitary-gonadal axis

George, A. J.·Hoffiz, Y. C.·Ware, C.·Dong, B.·Fang, N.·Hrabovszky, E.·Mabb, A. M.
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Abstract

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. HighlightsO_LIRnf216/Triad3 controls Gnrh and intrinsic hypothalamic cell activity C_LIO_LIRnf216/Triad3 knockout male mice have greater reproductive impairments than females C_LIO_LIRnf216/Triad3 controls the HPG axis at multiple levels C_LI

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George, A. J., Hoffiz, Y. C., Ware, C., Dong, B., Fang, N., Hrabovszky, E., Mabb, A. M.. 2021-03-21. The E3 ubiquitin ligase RNF216/TRIAD3 is a central regulator of the hypothalamic-pituitary-gonadal axis. https://doi.org/10.1101/2021.03.21.436306

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