摘要：SummaryRecessive mutations inRNF216/TRIAD3cause Gordon Holmes syndrome (GHS), in which dysfunction of the hypothalamic-pituitary-gonadal (HPG) axis and neurodegeneration are thought to be core phenotypes. We knocked outRnf216/Triad3in a gonadotropin-releasing hormone (GnRH) hypothalamic cell line.Rnf216/Triad3knockout (KO) cells had decreased steady-state GnRH and calcium transients.Rnf216/Triad3KO 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 ofRnf216/Triad3in 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.Graphical abstractDisplay OmittedHighlights•Rnf216/Triad3controls GnRH production and intrinsic hypothalamic cell activity•Rnf216/Triad3knockout male mice have greater reproductive impairments than females•Rnf216/Triad3controls the HPG axis differently in males and females•Rnf216/Triad3knockout male mice have reactive microglia in the hypothalamusDisease; Biological sciences; Cell biology; Functional aspects of cell biology
