Loss of microRNA-7a2 induces hypogonadotropic hypogonadism and infertility (Mar 2017)

Loss of microRNA-7a2 induces hypogonadotropic hypogonadism and infertility
J Clin Invest. 2017 Mar 1;127(3):1061-1074
Kashan Ahmed, Mary P. LaPierre, Emanuel Gasser, Rémy Denzler, Yinjie Yang, Thomas Rülicke, Jukka Kero, Mathieu Latreille, and Markus Stoffel
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Short description:
Sexual maturation and reproduction are regulated by the hypothalamus, pituitary, and gonads. These endocrine organs form an integrated system known as the hypothalamic-pituitary-gonadal (HPG) axis, which is responsible for the adequate secretion of male and female sex hormones (1). The endocrine components of the reproductive system are hierarchically organized and integrated in a classical endocrine feedback loop. The HPG axis is active during development and shortly after birth, silenced during childhood by inhibitory neurotransmitters, and reawakened at the onset of puberty by pulsatile secretion of gonadotropin-releasing hormone (GnRH), a decapeptide that is synthesized by neurons located in the mediobasal hypothalamus (2, 3). During development, GnRH neurons originate from the olfactory placode of the olfactory system and migrate to the hypothalamus, where they control reproduction by secreting GnRH into a capillary network that transmits GnRH to the anterior pituitary to stimulate secretion of follicle-stimulating hormone (FSH, encoded by Fshb) and luteinizing hormone (LH, encoded by Lhb). Secreted GnRH acts via the GnRH receptor, which is expressed on gonadotropic cells in the anterior pituitary gland. This action regulates synthesis and release of both gonadotropins, LH and FSH, that control gonadal maturation and adult reproductive physiology via stimulation of sex steroid synthesis (1). In males, FSH stimulates proliferation of immature Sertoli cells and spermatogonia, whereas LH stimulates Leydig cells to produce testosterone (4). In females, LH triggers ovulation, promotes development of the corpus luteum, and stimulates theca cells to produce androgens, whereas FSH stimulates recruitment of secondary ovarian follicles and the secretion of estradiol from granulosa cells, thereby promoting follicular maturation, which ultimately leads to ovulation (5)
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Abstract taken from PubMed

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 have reported 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 or ovaries, impaired spermatogenesis, and lack of ovulation in male and female mice, respectively. We found that miR-7a2 is highly expressed in the pituitary, where it suppresses golgi glycoprotein 1 (GLG1) expression and downstream bone morphogenetic protein 4 (BMP4) signaling and also reduces expression of the prostaglandin F2a receptor negative regulator (PTGFRN), an inhibitor of prostaglandin signaling and follicle-stimulating hormone (FSH) and luteinizing hormone (LH) secretion. Our results reveal that miR-7a2 critically regulates sexual maturation and reproductive function by interconnecting miR-7 genomic circuits that regulate FSH and LH synthesis and secretion through their effects on pituitary prostaglandin and BMP4 signaling.
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