title: MicroRNA-181a suppresses mouse granulosa cell proliferation by targeting activin receptor IIA.
abstract: Activin, a member of the transforming growth factor-β superfamily, promotes the growth of preantral follicles and the proliferation of granulosa cells. However, little is known about the role of microRNAs in activin-mediated granulosa cell proliferation. Here, we reported a dose- and time-dependent suppression of microRNA-181a (miR-181a) expression by activin A in mouse granulosa cells (mGC). Overexpression of miR-181a in mGC suppressed activin receptor IIA (acvr2a) expression by binding to its 3'-untranslated region (3'-UTR), resulting in down-regulation of cyclin D2 and proliferating cell nuclear antigen expression, leading to inhibition of the cellular proliferation, while overexpression of acvr2a attenuated the suppressive effect of miR-181a on mGC proliferation. Consistent with the inhibition of acvr2a expression, miR-181a prevented the phosphorylation of the activin intracellular signal transducer, mothers against decapentaplegic homolog 2 (Smad2), leading to the inactivation of activin signaling pathway. Interestingly, we found that miR-181a expression decreased in ovaries of mice at age of 8, 12, and 21 days, as compared with that in ovaries of 3-day old mice, and its level was reduced in preantral and antral follicles of mice compared with that in primary ones. Moreover, the level of miR-181a in the blood of patients with premature ovarian failure was significantly increased compared with that in normal females. This study identifies an interplay between miR-181a and acvr2a, and reveals an important role of miR-181a in regulating granulosa cell proliferation and ovarian follicle development.
authors.affiliation: Reproductive Medicine Center, Department of Obstetrics and Gynecology, Nanjing Drum Tower Hospital, Nanjing University Medical School, Nanjing, China.
authors.forename: Qun
authors.initials: Q
authors.lastname: Zhang
authors.forename: Haixiang
authors.initials: H
authors.lastname: Sun
authors.forename: Yue
authors.initials: Y
authors.lastname: Jiang
authors.forename: Lijun
authors.initials: L
authors.lastname: Ding
authors.forename: Shaogen
authors.initials: S
authors.lastname: Wu
authors.forename: Ting
authors.initials: T
authors.lastname: Fang
authors.forename: Guijun
authors.initials: G
authors.lastname: Yan
authors.forename: Yali
authors.initials: Y
authors.lastname: Hu
mesh_terms: D030301:Activin Receptors, Type II / Q000378:metabolism*; D028341:Activins / Q000494:pharmacology*; D000704:Analysis of Variance; D000818:Animals; D015153:Blotting, Western; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects*; D056742:Cyclin D2 / Q000378:metabolism; D017931:DNA Primers / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D005260:Female; D006107:Granulosa Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D008156:Luciferases; D051379:Mice; D008813:Mice, Inbred ICR; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D008856:Microscopy, Fluorescence; D009841:Oligonucleotides / Q000235:genetics; D006080:Ovarian Follicle / Q000187:drug effects / Q000254:growth & development*; D010766:Phosphorylation / Q000187:drug effects; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects*; D051899:Smad2 Protein / Q000378:metabolism; D013997:Time Factors
chemical_list: C486196:Ccnd2 protein, mouse; D056742:Cyclin D2; D017931:DNA Primers; D035683:MicroRNAs; D009841:Oligonucleotides; D018809:Proliferating Cell Nuclear Antigen; D051899:Smad2 Protein; C422405:activin A; C529100:mirn181 microRNA, mouse; D028341:Activins; D008156:Luciferases; D030301:Activin Receptors, Type II; C425585:activin receptor type II-A