iScience
Volume 25, Issue 6, 17 June 2022, 104386
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Article
The E3 ubiquitin ligase RNF216/TRIAD3 is a key coordinator of the hypothalamic-pituitary-gonadal axis

https://doi.org/10.1016/j.isci.2022.104386Get rights and content
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Highlights

  • Rnf216/Triad3 controls GnRH production and intrinsic hypothalamic cell activity

  • Rnf216/Triad3 knockout male mice have greater reproductive impairments than females

  • Rnf216/Triad3 controls the HPG axis differently in males and females

  • Rnf216/Triad3 knockout male mice have reactive microglia in the hypothalamus

Summary

Recessive mutations in RNF216/TRIAD3 cause Gordon Holmes syndrome (GHS), in which dysfunction of the hypothalamic-pituitary-gonadal (HPG) axis and neurodegeneration are thought to be core phenotypes. We knocked out Rnf216/Triad3 in a gonadotropin-releasing hormone (GnRH) hypothalamic cell line. Rnf216/Triad3 knockout (KO) cells had decreased steady-state GnRH and calcium transients. Rnf216/Triad3 KO adult mice had reductions in GnRH neuron soma size and GnRH production without changes in neuron densities. In addition, KO male mice had smaller testicular volumes that were accompanied by an abnormal release of inhibin B and follicle-stimulating hormone, whereas KO females exhibited irregular estrous cycling. KO males, but not females, had reactive microglia in the hypothalamus. Conditional deletion of Rnf216/Triad3 in neural stem cells caused abnormal microglia expression in males, but reproductive function remained unaffected. Our findings show that dysfunction of RNF216/TRIAD3 affects the HPG axis and microglia in a region- and sex-dependent manner, implicating sex-specific therapeutic interventions for GHS.

Subject areas

Disease
Biological sciences
Cell biology
Functional aspects of cell biology

Data and code availability

All data reported in this paper will be shared by the lead contact upon request.

This paper does not report original code.

Any additional information required to reanalyze data reported in this paper is available from the lead contact upon request.

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