Liver Receptor Homolog-1 Regulates Kisspeptin Expression in the Arcuate Nucleus to Promote Reproductive Axis Function



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The timing of ovulation in mammals is set by a complex hypothalamic pituitary neuroendocrine axis. Kisspeptin neurons in the arcuate nucleus (Arc) are thought to secrete kisspeptin (Kiss1) to stimulate the release of follicle stimulating hormone (FSH) from the pituitary. However, mechanisms that drive Arc KISS1 output and maintain adequate FSH secretion required for folliculogenesis are not well understood. Here, we report that the nuclear receptor, liver receptor homolog-1 (LRH-1), is expressed in kisspeptin neurons of the Arc. Kiss1 is found to be a direct target gene of LRH-1, whereby LRH-1 sets a basal tone of kiss1 expression in the Arc. Deletion of Lrh-1 from kisspeptin neurons causes decreased Arc Kiss1 expression. This leads to reduced plasma FSH, prolongation of the estrous cycle, and decreased follicle maturation and ovulation. These defects ultimately compromise fertility. Overexpression of Lrh-1 in a kisspeptin neuron-specific transgenic mouse model increases Arc Kiss1 expression and plasma FSH. Chromatin immunoprecipitation and luciferase-based promoter assays demonstrate that LRH-1 binds to a putative LRH-1 response element in the Kiss1 promoter to stimulate activity. In conclusion, LRH-1 is expressed in the Arc to set the basal tone of Kiss1 output needed to promote FSH secretion for folliculogenesis prior to ovulation.

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