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Impaired microRNA processing causes corpus luteum insufficiency and infertility in mice
Motoyuki Otsuka, … , Shengcai Lin, Jiahuai Han
Motoyuki Otsuka, … , Shengcai Lin, Jiahuai Han
Published April 8, 2008
Citation Information: J Clin Invest. 2008;118(5):1944-1954. https://doi.org/10.1172/JCI33680.
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Research Article Reproductive biology

Impaired microRNA processing causes corpus luteum insufficiency and infertility in mice

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Abstract

The microRNA (miRNA) processing enzyme Dicer1 is required for zygotic and embryonic development, but the early embryonic lethality of Dicer1 null alleles in mice has limited our ability to address the role of Dicer1 in normal mouse growth and development. To address this question, we used a mouse mutant with a hypomorphic Dicer1 allele (Dicerd/d) and found that Dicer1 deficiency resulted in female infertility. This defect in female Dicerd/d mice was caused by corpus luteum (CL) insufficiency and resulted, at least in part, from the impaired growth of new capillary vessels in the ovary. We found that the impaired CL angiogenesis in Dicerd/d mice was associated with a lack of miR17-5p and let7b, 2 miRNAs that participate in angiogenesis by regulating the expression of the antiangiogenic factor tissue inhibitor of metalloproteinase 1. Furthermore, injection of miR17-5p and let7b into the ovaries of Dicerd/d mice partially normalized tissue inhibitor of metalloproteinase 1 expression and CL angiogenesis. Our data indicate that the development and function of the ovarian CL is a physiological process that appears to be regulated by miRNAs and requires Dicer1 function.

Authors

Motoyuki Otsuka, Min Zheng, Masaaki Hayashi, Jing-Dwan Lee, Osamu Yoshino, Shengcai Lin, Jiahuai Han

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Figure 3

TIMP1 expression is elevated in Dicerd/d female mice ovaries.

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TIMP1 expression is elevated in Dicerd/d female mice ovaries.
   
(A) Mo...
(A) Mouse angiogenesis-related antibody arrays hybridized with ovarian lysates from Dicer+/+ and Dicerd/d mice on day 1.5 after coitus. Two independent experiments using different Dicer+/+ and Dicerd/d littermate mice pairs were performed. A representative image is shown. The positions of TIMP1 are denoted by boxes and arrows. The positive loading controls are also denoted by boxes and arrows. The map of antibodies spotted on these arrays is shown below. (B) Signal intensity ratios of each gene between Dicer+/+ and Dicerd/d mice ovaries obtained by protein array analyses. The normalized signal intensities of each protein from Dicerd/d mice ovaries were divided by those from Dicer+/+ mice ovaries. Four values for each gene obtained from 2 independent experimental sets were used for the analysis. The data are expressed as mean ± SD. Genes with low signal intensity that could not be analyzed further are expressed as N.D. (not determined). The mean signal intensities of TIMP1 in Dicerd/d mice ovaries are more than 2-fold those in Dicer+/+ mice. (C) The distribution of log10 conversion values of the average of normalized signal intensities (n = 4) from each protein is shown as a scatter plot. The solid lines indicate the position of 2-fold changes in the intensities. The results for TIMP1 and platelet factor 4 are indicated by arrows. (D) Verification of Dicer1 protein deficiency and TIMP1 protein upregulation in Dicerd/d mice ovaries. Dicer1 and TIMP1 protein expression in the ovaries of 2 separate Dicerd/d and Dicer+/+ littermate mice on day 1.5 after coitus are shown. GAPDH was used as a loading control.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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