title: Rac1 modulates the formation of primordial follicles by facilitating STAT3-directed Jagged1, GDF9 and BMP15 transcription in mice.
abstract: The size of the primordial follicle pool determines the reproductive potential of mammalian females, and establishment of the pool is highly dependent on specific genes expression. However, the molecular mechanisms by which the essential genes are regulated coordinately to ensure primordial follicle assembly remain a mystery. Here, we show that the small GTPase Rac1 plays an indispensable role in controlling the formation of primordial follicles in mouse ovary. Employing fetal mouse ovary organ culture system, we demonstrate that disruption of Rac1 retarded the breakdown of germline cell cysts while Rac1 overexpression accelerated the formation of primordial follicles. In addition, in vivo inhibitor injection resulted in the formation of multi-oocyte follicles. Subsequent investigation showed that Rac1 induced nuclear import of STAT3 by physical binding. In turn, nuclear STAT3 directly activated the transcription of essential oocyte-specific genes, including Jagged1, GDF9, BMP15 and Nobox. Further, GDF9 and BMP15 regulated the translation of Notch2 via mTORC1 activation in pregranulosa cells. Overexression or addition of Jagged1, GDF9 and BMP15 not only reversed the effect of Rac1 disruption, but also accelerated primordial follicle formation via Notch2 signaling activation. Collectively, these results indicate that Rac1 plays important roles as a key regulator in follicular assembly.
authors.affiliation: State Key Laboratory of Agrobiotechnology, College of Biological Sciences, China Agricultural University, Beijing, 100193, China.
authors.forename: Lihua
authors.initials: L
authors.lastname: Zhao
authors.affiliation: State Key Laboratory of Agrobiotechnology, College of Biological Sciences, China Agricultural University, Beijing, 100193, China.
authors.forename: Xinhua
authors.initials: X
authors.lastname: Du
authors.affiliation: State Key Laboratory of Agrobiotechnology, College of Biological Sciences, China Agricultural University, Beijing, 100193, China.
authors.forename: Kun
authors.initials: K
authors.lastname: Huang
authors.affiliation: State Key Laboratory of Agrobiotechnology, College of Biological Sciences, China Agricultural University, Beijing, 100193, China.
authors.forename: Tuo
authors.initials: T
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Agrobiotechnology, College of Biological Sciences, China Agricultural University, Beijing, 100193, China.
authors.forename: Zhen
authors.initials: Z
authors.lastname: Teng
authors.affiliation: State Key Laboratory of Agrobiotechnology, College of Biological Sciences, China Agricultural University, Beijing, 100193, China.
authors.forename: Wanbao
authors.initials: W
authors.lastname: Niu
authors.affiliation: State Key Laboratory of Agrobiotechnology, College of Biological Sciences, China Agricultural University, Beijing, 100193, China.
authors.forename: Chao
authors.initials: C
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Agrobiotechnology, College of Biological Sciences, China Agricultural University, Beijing, 100193, China.
authors.forename: Guoliang
authors.initials: G
authors.lastname: Xia
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000235:genetics; D000634:Aminoquinolines / Q000494:pharmacology; D000818:Animals; D015153:Blotting, Western; D055430:Bone Morphogenetic Protein 15 / Q000235:genetics / Q000378:metabolism*; D002467:Cell Nucleus / Q000378:metabolism; D005260:Female; D018507:Gene Expression Regulation, Developmental; D055429:Growth Differentiation Factor 9 / Q000235:genetics / Q000378:metabolism*; D007150:Immunohistochemistry; D000072100:Jagged-1 Protein / Q000235:genetics / Q000378:metabolism*; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D008957:Models, Genetic; D046912:Multiprotein Complexes / Q000235:genetics / Q000378:metabolism; D009924:Organ Culture Techniques; D006080:Ovarian Follicle / Q000187:drug effects / Q000196:embryology / Q000378:metabolism*; D011485:Protein Binding; D011743:Pyrimidines / Q000494:pharmacology; D034622:RNA Interference; D051883:Receptor, Notch2 / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic; D020830:rac1 GTP-Binding Protein / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
chemical_list: D000634:Aminoquinolines; C525902:Bmp15 protein, mouse; D055430:Bone Morphogenetic Protein 15; C525898:Gdf9 protein, mouse; D055429:Growth Differentiation Factor 9; D000072100:Jagged-1 Protein; D046912:Multiprotein Complexes; C487513:NSC 23766; C497765:Notch2 protein, mouse; D011743:Pyrimidines; D051883:Receptor, Notch2; D050796:STAT3 Transcription Factor; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases; D020830:rac1 GTP-Binding Protein