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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Impaired microRNA processing causes corpus luteum insufficiency and infertility in mice

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 2

Impaired angiogenesis in the CLs of Dicerd/d mice.

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Impaired angiogenesis in the CLs of Dicerd/d mice. (A) Ovarian tissu...
(A) Ovarian tissue sections obtained from Dicer+/+ and Dicerd/d mice on day 1.5 of pregnancy were stained with H&E (original magnification, ×100). CLs in Dicer+/+ and Dicerd/d mice ovaries is denoted by the boxes and are shown at higher original magnification (×400, bottom). The cells had less cytoplasm and less vascularity in the CLs of Dicerd/d mice. (B) Immunofluorescence analyses of ovaries from Dicerd/d and Dicer+/+ mice on day 1.5 of pregnancy show the localization of type IV collagen — a marker of the basal lamina of endothelial cells. Close examination of the vascular network in the CLs denoted by the boxes (top) is shown at higher magnification (×400; bottom). Dicer+/+ CLs showed more filamentous and punctuated collagen IV staining, which indicated higher vessel densities than those in Dicerd/d mice. (C) PECAM (CD31) immunofluorescence staining of CLs in Dicerd/d and Dicer+/+ mice on day 1.5 of pregnancy. The number and the length of the vessels were greater and longer in Dicer+/+ CLs. Original magnification, ×400. (D) Cumulative vessel length in CLs was determined as the average of the number of vessels per 100 × 100 μm2 multiplied by the vessel length in 3 random fields. The results of type IV collagen immunofluorescence staining from 4 different Dicer+/+ and Dicerd/d pairs were used. The data are expressed as mean ± SD. *P = 0.0012.