title: Loss of microRNA-7a2 induces hypogonadotropic hypogonadism and infertility.
abstract: 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.
authors.forename: Kashan
authors.initials: K
authors.lastname: Ahmed
authors.forename: Mary P
authors.initials: MP
authors.lastname: LaPierre
authors.forename: Emanuel
authors.initials: E
authors.lastname: Gasser
authors.forename: Rémy
authors.initials: R
authors.lastname: Denzler
authors.forename: Yinjie
authors.initials: Y
authors.lastname: Yang
authors.forename: Thomas
authors.initials: T
authors.lastname: Rülicke
authors.forename: Jukka
authors.initials: J
authors.lastname: Kero
authors.forename: Mathieu
authors.initials: M
authors.lastname: Latreille
authors.forename: Markus
authors.initials: M
authors.lastname: Stoffel
mesh_terms: D000818:Animals; D055415:Bone Morphogenetic Protein 4 / Q000235:genetics / Q000378:metabolism; D005260:Female; D005640:Follicle Stimulating Hormone / Q000235:genetics / Q000378:metabolism; D012739:Gonadal Steroid Hormones / Q000235:genetics / Q000378:metabolism; D007006:Hypogonadism / Q000235:genetics / Q000378:metabolism*; D007030:Hypothalamo-Hypophyseal System / Q000378:metabolism*; D007246:Infertility / Q000235:genetics / Q000378:metabolism*; D007986:Luteinizing Hormone / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D010053:Ovary / Q000378:metabolism; D017468:Receptors, Fibroblast Growth Factor / Q000235:genetics / Q000378:metabolism; D012795:Sialoglycoproteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D013737:Testis / Q000378:metabolism
chemical_list: C525810:Bmp4 protein, mouse; D055415:Bone Morphogenetic Protein 4; D012739:Gonadal Steroid Hormones; C549243:MIRN7 microRNA, mouse; D035683:MicroRNAs; D017468:Receptors, Fibroblast Growth Factor; D012795:Sialoglycoproteins; C086711:cysteine-rich fibroblast growth factor receptor; D007986:Luteinizing Hormone; D005640:Follicle Stimulating Hormone