title: Deficiency in DGCR8-dependent canonical microRNAs causes infertility due to multiple abnormalities during uterine development in mice.
abstract: DGCR8 is an RNA-binding protein that interacts with DROSHA to produce pre-microRNA in the nucleus, while DICER generates not only mature microRNA, but also endogenous small interfering RNAs in the cytoplasm. Here, we produced Dgcr8 conditional knock-out mice using progesterone receptor (PR)-Cre (Dgcr8(d/d)) and demonstrated that canonical microRNAs dependent on the DROSHA-DGCR8 complex are required for uterine development as well as female fertility in mice. Adult Dgcr8(d/d) females neither underwent regular reproductive cycles nor produced pups, whereas administration of exogenous gonadotropins induced normal ovulation in these mice. Interestingly, immune cells associated with acute inflammation aberrantly infiltrated into reproductive organs of pregnant Dgcr8(d/d) mice. Regarding uterine development, multiple uterine abnormalities were noticeable at 4 weeks of age when PR is significantly increased, and the severity of these deformities increased over time. Gland formation and myometrial layers were significantly reduced, and the stromal cell compartment did not expand and became atrophic during uterine development in these mice. These results were consistent with aberrantly reduced stromal cell proliferation and completely failed decidualization. Collectively, we suggest that DGCR8-dependent canonical microRNAs are essential for uterine development and physiological processes such as proper immune modulation, reproductive cycle, and steroid hormone responsiveness in mice.
authors.affiliation: Department of Biomedical Science, CHA University, Seongnam, Gyeonggi, 463-400 Korea.
authors.forename: Yeon Sun
authors.initials: YS
authors.lastname: Kim
authors.affiliation: Department of Biomedical Science, CHA University, Seongnam, Gyeonggi, 463-400 Korea.
authors.forename: Hye-Ryun
authors.initials: HR
authors.lastname: Kim
authors.affiliation: Department of Pharmacology and Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul 120-752, Korea.
authors.forename: Hyongbum
authors.initials: H
authors.lastname: Kim
authors.affiliation: Department of Biomedical Science, CHA University, Seongnam, Gyeonggi, 463-400 Korea.
authors.forename: Seung Chel
authors.initials: SC
authors.lastname: Yang
authors.affiliation: Department of Biomedical Science, CHA University, Seongnam, Gyeonggi, 463-400 Korea.
authors.forename: Mira
authors.initials: M
authors.lastname: Park
authors.affiliation: Fertility Center of CHA Gangnam Medical Center, CHA University, Seoul, Korea.
authors.forename: Jung Ah
authors.initials: JA
authors.lastname: Yoon
authors.affiliation: Department of Veterinary Medicine, College of Veterinary Medicine, Konkuk University, Seoul, 143-701 Korea.
authors.forename: Hyunjung J
authors.initials: HJ
authors.lastname: Lim
authors.affiliation: Department of Internal Medicine, School of Medicine, Stem Cell Institute, Kangwon National University, Chuncheon, Kangwon 200-701, Korea.
authors.forename: Seok-Ho
authors.initials: SH
authors.lastname: Hong
authors.affiliation: Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas, 77030 USA.
authors.forename: Francesco J
authors.initials: FJ
authors.lastname: DeMayo
authors.affiliation: Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas, 77030 USA.
authors.forename: John P
authors.initials: JP
authors.lastname: Lydon
authors.affiliation: Department of Biomedical Science, CHA University, Seongnam, Gyeonggi, 463-400 Korea.
authors.forename: Youngsok
authors.initials: Y
authors.lastname: Choi
authors.affiliation: Department of Biomedical Science, CHA University, Seongnam, Gyeonggi, 463-400 Korea.|Fertility Center of CHA Gangnam Medical Center, CHA University, Seoul, Korea.
authors.forename: Dong Ryul
authors.initials: DR
authors.lastname: Lee
authors.affiliation: Department of Biomedical Science, CHA University, Seongnam, Gyeonggi, 463-400 Korea.|Fertility Center of CHA Gangnam Medical Center, CHA University, Seoul, Korea.
authors.forename: Haengseok
authors.initials: H
authors.lastname: Song
mesh_terms: D000015:Abnormalities, Multiple / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D049109:Cell Proliferation; D003338:Corpus Luteum; D004195:Disease Models, Animal; D030762:Estrous Cycle / Q000235:genetics; D005260:Female; D005786:Gene Expression Regulation; D012739:Gonadal Steroid Hormones / Q000378:metabolism; D007246:Infertility / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D035683:MicroRNAs / Q000235:genetics*; D009865:Oocytes / Q000378:metabolism; D009928:Organ Specificity / Q000235:genetics; D038081:Organogenesis / Q000235:genetics; D011247:Pregnancy; D016601:RNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D017154:Stromal Cells / Q000378:metabolism; D014564:Urogenital Abnormalities / Q000235:genetics* / Q000378:metabolism; D014599:Uterus / Q000002:abnormalities* / Q000378:metabolism
chemical_list: C474044:Dgcr8 protein, mouse; D012739:Gonadal Steroid Hormones; D035683:MicroRNAs; D016601:RNA-Binding Proteins
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