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Mol Endocrinol. 2015 Mar;29(3):364-72. doi: 10.1210/me.2014-1390. Epub 2015 Jan 30.

Rapid communication: A microRNA-132/212 pathway mediates GnRH activation of FSH expression.

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Department of Biologie Fonctionnelle et Adaptative, Université Paris-Diderot, Sorbonne Paris Cité, F-75013 Paris, France; Centre National pour la Recherche Scientifique Unité Mixte de Recherche 8251, F-75013 Paris, France; and Institut National de la Santé et de la Recherche Médicale Unité 1133, Physiologie de l'axe Gonadotrope, F-75013 Paris, France.


GnRH plays a key role in the vertebrate reproductive system by stimulating biosynthesis and secretion of pituitary gonadotropins. However, the potential involvement of microRNAs (miRNAs) on this activation has still to be explored. In this study, we investigated the role of miRNA-132 and miRNA-212, two tandemly expressed miRNAs that target the same transcripts, on GnRH-induced FSH expression. We first showed that the GnRH stimulation of FSH secretion was reduced and Fshb mRNA abolished by blocking miR-132/212 action in rat pituitary cells. In mouse LβT2 gonadotrope cells, the GnRH stimulation of Fshb mRNA was also demonstrated to be dependent on miR-132/212 and reproduced by overexpressing one or both miRNAs. We then showed that the miR-132/212-mediated action of GnRH involved a posttranscriptional decrease of sirtuin 1 (SIRT1) deacetylase. The lower level of SIRT1 deacetylase correlated with an increase in the acetylated form of Forkhead Box O1 (FOXO1), a transcriptional repressor of Fshb. Interestingly, we show that the acetylated mimicking mutant of FOXO1 was localized outside the nucleus, thus alleviating its repressive effect on Fshb transcription. Overall, we demonstrate that the GnRH stimulation of Fshb expression is dependent on miR-132/212 and involves a SIRT1-FOXO1 pathway. This is the first demonstration of an obligatory microRNA pathway in the GnRH-regulated expression of a gonadotropin gene.

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