ECE2019 Symposia Congenital hypogonadotropic hypogonadism: New insights into GnRH Regulation (3 abstracts)
Switzerland.
A sparse population of a few hundred primarily hypothalamic neurons forms the hub of a complex neuroglial network that controls reproduction in mammals by secreting the master molecule, gonadotropin-releasing hormone (GnRH). Both the Kisspeptin input on GnRH neurons and timely changes in GnRH expression are necessary for the onset of puberty. However, the exact molecular mechanisms underlying this process remain elusive. Here, we report that a dramatic inversion in microRNA expression profile within postnatal GnRH neurons acts as an epigenetic switch that triggers the prepubertal increase in GnRH expression and controls the ability of GnRH neurons to sense Kisspeptin input, for a correct initiation of puberty. The disabling of this microRNA-mediated switch leads to hypogonadotropic hypogonadism and infertility in mice. The underlying mechanism involves a complex and multilayered network of transcriptional activators and repressors reciprocally controlled by several microRNA species, including miR-200 and miR-155. These microRNAs tune the balance between inductive and repressive signals to trigger a rise in hypothalamic GnRH expression and to control the expression of Kisspeptin receptor. Anomalies in this microRNA-embedded genetic network, which appears essential for the neuroendocrine control of reproduction by controlling both Kisspeptin sensitivity and GnRH production, could thus underlie dysfunctions of human puberty and fertility when a genetic cause is not apparent.