Loss of microRNA-7a2 induces hypogonadotropic hypogonadism and infertility
Kashan Ahmed, … , Mathieu Latreille, Markus Stoffel
Kashan Ahmed, … , Mathieu Latreille, Markus Stoffel
Published February 20, 2017
Citation Information: J Clin Invest. 2017;127(3):1061-1074. https://doi.org/10.1172/JCI90031.
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Research Article Endocrinology Reproductive biology

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

Kashan Ahmed, Mary P. LaPierre, Emanuel Gasser, Rémy Denzler, Yinjie Yang, Thomas Rülicke, Jukka Kero, Mathieu Latreille, Markus Stoffel

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Figure 3

Constitutive genetic ablation of mir-7a2 causes hypogonadotropic hypogonadism.

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Constitutive genetic ablation of mir-7a2 causes hypogonadotropic hypogon...
(A) Expression of pituitary hormones in male mir-7a2 KO or control mice shown as heat map analysis from RNA-Seq (WT, mir-7a2 KO, n = 3). (B and C) Representative immunohistological images of pituitary sections (n = 3) stained for LH (B) or FSH (C) of control (upper images) or mir-7a2 KO mice (lower images). Scale bars: 200 μm. (D and E) Quantification of LH-positive (D) or FSH-positive (E) cells in pituitary of mir-7a2 KO or control mice (WT, mir-7a2 KO, n = 3). (F and G) Pituitary weights of male (F) or female (G) mir-7a1 KO, mir-7a2 KO, or respective control mice (males, mir-7a1 control, mir-7a1 KO, n = 4; mir-7a2 control, mir-7a2 KO, n = 8; mir-7a1 control, n = 8; mir-7a1 KO, n = 10; mir-7a2 control, n = 6; mir-7a2 KO, n = 7). (H and I) Plasma levels of FSH (H) or LH (I) in male mir-7a2 KO or control mice (WT, mir-7a2 KO, n = 7). (J and K) Plasma levels of FSH (J) or LH (K) in female mir-7a2 KO or control mice (WT, mir-7a2 KO, n = 4). (L) Number of oocytes collected after superovulation test in 5-week-old mir-7a2 KO or control mice (WT, n = 4; mir-7a2 KO, n = 3). All data are represented as mean ± SD except in (H, K), where data are represented as ± SEM. *P < 0.05; **P < 0.01; ***P < 0.001, ANOVA (F, G); t test (D, E, H, I, J, K).