Editors' ChoicePhysiology

Micromanaging puberty

Sci. Signal.  07 Jun 2016:
Vol. 9, Issue 431, pp. ec134
DOI: 10.1126/scisignal.aag2871

The axis comprising the hypothalamus, pituitary, and gonads directs the development of reproductive function in mammals. Sexual maturity (puberty) is regulated by the timely induction of expression of the gene encoding gonadotropin-releasing hormone (GnRH) in a small set of hypothalamic neurons. Mice undergo an infantile to juveniles transition from ~ postnatal days 7 to 12 (P7-P12). Messina et al. discovered that a microRNA (miRNA)–mediated mechanism triggers the switch from repression to induction of GnRH. Transgenic mice lacking Dicer, a protein that processes precursor microRNAs into their active smaller forms, in GnRH neurons were infertile and lacked Gnrh expression. Expressing a green fluorescent protein reporter for the Gnrh promoter in Dicer-deficient mice revealed that the Gnrh promoter was repressed. In GnRH neurons in wild-type mice, the abundance of mRNA encoding several transcription factors that bind the Gnrh promoter and activate its expression increased as the infant mice matured between P7 and P12. However, GnRH neurons in the Dicer-deficient mice had decreased abundance of these transcriptional activators but markedly increased abundance of transcription factors that bind and repress the Gnrh promoter. The abundance of miRNAs that target mRNAs encoding transcription factors that bind the Gnrh had inverted expression profiles in GnRH neurons from P7 and P12 wild-type mice, such that the abundance of transcriptional activators increased over this period and the abundance of transcriptional repressors decreased. Two miRNAs reduced the abundance of transcripts encoding C/EBPβ (miR-155) and ZEB1 (miR-200) in P12 mice. C/EBPβ and ZEB1 are both transcription factors, but whether they promote or repress gene expression can be context specific. In GnRH neurons, C/EBPβ promoted ZEB1 expression, and ZEB1 repressed both Gnrh and various other genes encoding transcription factors that promote Gnrh expression. Both C/EBPβ and ZEB1 have binding sites in the promoter of the gene encoding kisspeptin receptor GPR54, which stimulates the nuclear translocation of OTX2, a transcription factor that promotes Gnrh expression. GnRH neurons from Dicer-deficient mice had less GPR54, which would decrease Gnrh expression. This effect on GPR54 suggested that C/EBPβ and ZEB1 acted as repressors at the Gpr54 gene and that the miRNAs reduced their abundance, enabling Gpr54 expression. Neuronal nitric oxide (NO) synthesis, which is stimulated by kisspeptin-GPR54 signaling, promotes sexual maturation in mice; however, NO can repress Gnrh expression when C/EBPβ is abundant. Intraperitoneal injection of an NO synthase inhibitor restored Gnrh expression in Dicer-deficient mice, suggesting that a main role of miRNA network is to control C/EBPβ abundance and thereby control the ability of kisspeptin to stimulate the onset of puberty.

A. Messina, F. Langlet, K. Chachlaki, J. Roa, S. Rasika, N. Jouy, S. Gallet, F. Gaytan, J. Parkash, M. Tena-Sempere, P. Giacobini, V. Prevot, A microRNA switch regulates the rise in hypothalamic GnRH production before puberty. Nat. Neurosci. 19, 835–844 (2016). [PubMed]

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