Impaired microRNA processing causes corpus luteum insufficiency and infertility in mice.
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 (Dicer(d/d)) and found that Dicer1 deficiency resulted in female infertility. This defect in female Dicer(d/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 Dicer(d/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 Dicer(d/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.
Otsuka
Motoyuki
M
Department of Immunology, The Scripps Research Institute, La Jolla, California 92037, USA.
Zheng
Min
M
Hayashi
Masaaki
M
Lee
Jing-Dwan
JD
Yoshino
Osamu
O
Lin
Shengcai
S
Han
Jiahuai
J
D000483:Alleles; D000818:Animals; D001483:Base Sequence; D003338:Corpus Luteum / Q000098:blood supply / Q000378:metabolism / Q000473:pathology; D053487:DEAD-box RNA Helicases / Q000235:genetics / Q000378:metabolism; D004722:Endoribonucleases / Q000235:genetics / Q000378:metabolism; D005260:Female; D007247:Infertility, Female / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D046228:Microarray Analysis; D008969:Molecular Sequence Data; D018919:Neovascularization, Physiologic; D010053:Ovary / Q000033:anatomy & histology / Q000378:metabolism / Q000637:transplantation; D012323:RNA Processing, Post-Transcriptional; D043244:Ribonuclease III; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000235:genetics / Q000378:metabolism
D035683:MicroRNAs; D019715:Tissue Inhibitor of Metalloproteinase-1; D004722:Endoribonucleases; C509781:Dicer1 protein, mouse; D043244:Ribonuclease III; D053487:DEAD-box RNA Helicases