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A microRNA switch regulates the rise in hypothalamic GnRH production before puberty

2016; Nature Portfolio; Volume: 19; Issue: 6 Linguagem: Inglês

10.1038/nn.4298

1546-1726

Andrea Messina, Fanny Langlet, Konstantina Chachlaki, Juan Roa, Sowmyalakshmí Rasika, Nathalie Jouy, Sarah Gallet, Francisco Gaytán, Jyoti Parkash, Manuel Tena‐Sempere, Paolo Giacobini, Vincent Prévot,

Neuroendocrine regulation and behavior

The authors show that a gene expression switch operated by microRNAs regulates the control of puberty onset and adult fertility by the CNS by triggering increased hypothalamic Gnrh mRNA expression during the infantile period of postnatal development. 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). Timely postnatal changes in GnRH expression are essential for puberty and adult fertility. Here we report that a multilayered microRNA-operated switch with built-in feedback governs increased GnRH expression during the infantile-to-juvenile transition and that impairing microRNA synthesis in GnRH neurons leads to hypogonadotropic hypogonadism and infertility in mice. Two essential components of this switch, miR-200 and miR-155, respectively regulate Zeb1, a repressor of Gnrh transcriptional activators and Gnrh itself, and Cebpb, a nitric oxide–mediated repressor of Gnrh that acts both directly and through Zeb1, in GnRH neurons. This alteration in the delicate balance between inductive and repressive signals induces the normal GnRH-fuelled run-up to correct puberty initiation, and interfering with this process disrupts the neuroendocrine control of reproduction.