MiR-505-3p, a New Repressor of Puberty Onset in Female Mice

Abstract

Puberty onset is a complex trait regulated by multiple genetic and environmental factors. In this study, we narrowed a puberty-related QTL on chromosome X in female mice to a 1.7 Mb region and deduced that miR-505-3p was the functional gene.\n\nIn a GT1-7 cell line with stable overexpression of miR-505-3p (pGT1-7), both ribosomes and ribosome biogenesis pathways were affected, and the expression of some puberty-related genes was down-regulated. The amount of mRNA and protein products of the Srsf1 gene decreased by 50 percent, and the expression of puberty-related genes was rescued by the overexpression of Srsf1. With the down regulation of Srsf1 expression through shRNA, the mRNA accumulation of puberty-related genes decreased simultaneously in the GT1-7 cell line. The results of RIP-seq showed that SF2, the protein of the Srsf1 gene, primarily bound ribosome protein (RP) mRNAs in GT1-7 cells.\n\nmiR-505-3p knockout female mice showed earlier vaginal opening, higher serum gonadotrophin levels and higher expression of puberty-related and Srsf1 genes in the hypothalamus than their wild-type littermates. B6 female mice with ectopic expression of miR-505-3p in the hypothalamus showed significant growth retardance and later VO than wild types.\n\nThese results suggest that miR-505-3p may regulate puberty onset via the Srsf1 gene and RP expression, which reveals a new regulatory pathway in mammalian puberty onset involving microRNA, SF2 and ribosome proteins.\n\nAuthor summaryIn this study, we identified miR-505-3p in a puberty-related QTL on the X chromosome as a female puberty onset repressor using a positional cloning strategy.\n\nGT1-7 cell lines stably overexpressing miR-505-3p (pGT1-7) showed Kiss1 and GnRH down-regulation. We also identified Srsf1 as the functional target gene of miR-505-3p in GT1-7 cells. Compared to wild-type mice, miR-505-3p knockout female mice showed puberty onset four days sooner, along with the overexpression of miR-505-3p in the hypothalamus 2 days later. Thus, miR-505-3p is a new repressor of puberty onset in female mice.