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Nat Neurosci. 2016 Jun;19(6):835-44. doi: 10.1038/nn.4298. Epub 2016 May 2.

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

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Inserm, Laboratory of Development and Plasticity of the Neuroendocrine Brain, Jean-Pierre Aubert Research Centre, U1172, Lille, France.
University of Lille, FHU 1,000 Days for Health, School of Medicine, Lille, France.
Columbia University Medical Center and Berrie Diabetes Center, New York, New York, USA.
Department of Cell Biology, Physiology and Immunology, University of Cordoba, Cordoba, Spain.
Instituto Maimonides de Investigación Biomédica de Cordoba (IMIBIC/HURS), Cordoba, Spain.
CIBER Fisiopatología de la Obesidad y Nutrición, Instituto de Salud Carlos III, Cordoba, Spain.
Inserm UMR1141 - PROTECT (Promoting Research Oriented Towards Early CNS Therapies), Paris, France.


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.

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