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 2

Ablation of mir-7a2 leads to female hypogonadism and anovulation.

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Ablation of mir-7a2 leads to female hypogonadism and anovulation. (A and...
(A and B) Representative images of ovaries and uteri (A) and quantification of ovary weights (B) of mir-7a1 KO, mir-7a2 KO, or respective control mice (mir-7a1 control, n = 9; mir-7a1 KO, n = 10; mir-7a2 control, n = 7; mir-7a2 KO, n = 4). Scale bar: 5 mm. (C and D) Histological examination using H&E staining of ovaries of WT control (C) or mir-7a2 KO (D) mice (n = 4). CL, corpus luteum; LAF, large antral follicle; GF, growing follicle. Shown are representative images of 4 mice per genotype. Scale bar: 100 μm. (E) Relative expression levels of ovarian steroidogenic genes in mir-7a2 KO or control mice (WT, n = 6; mir-7a2 KO, n = 4). (F) Plasma estradiol levels of 8-week-old mir-7a2 KO or control mice (WT, n = 12; mir-7a2 KO, n = 11). All data are represented as mean ± SD. *P < 0.05; **P < 0.01; ***P < 0.001, ANOVA (B); t test (E, F).