MiR-199-3p modulates the onset of puberty in rodents probably by regulating the expression of Kiss1 via the p38 MAPK pathway.

The Kiss1 gene plays an indispensable role in modulating the onset of puberty and fertility in mammals. Although an increasing number of genetic and environmental factors that influence reproduction through Kiss1 have been identified, the function of microRNAs, a class of posttranscriptional regulators, in regulating Kiss1 expression remains poorly understood. This study aimed at investigating the mechanism by which Kiss1 expression is regulated by microRNAs. A simplified miRNome screen by a dual-fluorescence reporter system based on Kiss1 was performed to identify microRNAs that affect the expression of Kiss1. The expression patterns of the identified microRNAs during the period of murine sexual development were investigated, and only miR-199-3p was studied further. Aided by bioinformatics algorithms, miR-199-3p was demonstrated to be a repressor of Kiss1 expression, as it blocked the expression of Kiss1 through the p38 MAPK pathway by simultaneously inhibiting several targets in both GT1-7 cells and primary hypothalamic neurons. Both the inhibition of the p38 MAPK pathway by the intracerebroventricular administration of chemical agents in rats and the ectopic expression of miR-199-3p by lentivirus injection in the hypothalamus in mice delayed puberty onset and gonad development. Our results presented a novel regulatory mechanism of puberty onset which the sustained downregulation of miR-199-3p might gradually release the inhibition of the p38 MAPK/Fos/CREB/Kiss1 pathway during puberty development.