Loss of microRNA-7a2 induces hypogonadotropic hypogonadism and infertility

MicroRNAs (miRNAs) are negative modulators of gene expression that fine-tune numerous biological processes. miRNA loss-of-function rarely results in highly penetrant phenotypes but rather influences cellular responses to physiologic and pathophysiologic stresses. Here we report that a single member of the evolutionarily conserved miR-7 family, miR-7a2, is essential for normal pituitary development and hypothalamic-pituitary-gonadal (HPG)function in adulthood. Genetic deletion of mir-7a2 causes infertility with low levels of gonadotropic and sex steroid hormones, small testes/ovaries, impaired spermatogenesis and lack of ovulation in male and female mice, respectively. We show that miR-7a2 is highly expressed in the pituitary where it suppresses expression of golgi glycoprotein 1 (Glg1) and downstream bone morphogenetic protein 4 (BMP4) signaling, as well as the prostaglandin F2areceptor negative regulator (Ptgfrn), an inhibitor of prostaglandin signaling and FSH/LH secretion. Our results reveal that miR-7a2 is a critical regulator of sexual maturation and reproductive function by interconnecting miR-7genomic circuits that regulate FSH and LH synthesis and secretion impacting on pituitary prostaglandin and BMP4 signaling.