Fertility and puberty onset are controlled within the brain by a neural network that drives the secretion of gonadotropin-releasing hormone (GnRH) from hypothalamic neuroendocrine neurons. During postnatal development, various permissive signals must be integrated for the initiation of sexual maturation but the molecular events that orchestrate the timely activation of the GnRH neurons remain a major unsolved biological mystery. Increasing evidences point out Micro-RNAs (miRNAs) as a key regulatory layer that controls gene expression at the post-transcriptional level supporting crucial neurobiological events from the embryonic development to the adulthood but nothing is known about their putative role in the neuroendocrine control of reproduction.
Here, we investigate the role of miRNAs in the development and function of the GnRH system using conditional knockout mice with a targeted deletion of Dicer (GnRHDicerKO), an essential protein for miRNAs biogenesis, in GnRH neurons.
The analysis of GnRHDicerKO mice showed that a lack of miRNAs in GnRH neurons causes defective sexual development resulting in hypogonadotropic-hypogonadism and infertility in both males and females. The characterization of the embryonic development of GnRH system has shown no overt deficit in GnRH neuron migration or projections to the median eminence. Strikingly, immunofluorescent analyses combined with genetic labeling of GnRH neurons revealed a progressive loss of GnRH expression in the hypothalamus during the late infantile period in postnatal life probably due to an alteration of the genetic network controlling the GnRH promoter.
Indeed, miRNA and gene expression profiling on FACS isolated GnRH neurons show that GnRH neurons express a specific set of GnRH transcription modulators as well a discrete population of miRNAs at specific postnatal ages. Moreover bioinformatic analyses revealed that a subset of these miRNAs, organized in few conserved clusters, targets known activators and/or repressors of the GnRH promoter. Finally, gene expression analysis on GnRH neurons from GnRHDicerKO mice confirm that the lack of miRNAs cause a profound alteration of the expression profile of known GnRH transcription modulators and leads to a dramatic decrease of GnRH expression.
Altogether, these results shed light on a new role of miRNAs in neuroendocrine processes and point out a specific set of miRNAs as key component of the genetic network that controls GnRH promoter activity. This supports the modulation of GnRH expression levels according to the developmental clock and to specific environmental/physiological changes to contribute to the postnatal activation of GnRH neurons.
20 - 22 Sep 2014
European Society for Paediatric Endocrinology