title: Somatic cells initiate primordial follicle activation and govern the development of dormant oocytes in mice.
abstract: BACKGROUND
  The majority of oocytes in the mammalian ovary are dormant oocytes that are enclosed in primordial follicles by several somatic cells, which we refer to as primordial follicle granulosa cells (pfGCs). Very little is known, however, about how the pfGCs control the activation of primordial follicles and the developmental fates of dormant oocytes.
  
  
  RESULTS
  By targeting molecules in pfGCs with several mutant mouse models, we demonstrate that the somatic pfGCs initiate the activation of primordial follicles and govern the quiescence or awakening of dormant oocytes. Inhibition of mTORC1 signaling in pfGCs prevents the differentiation of pfGCs into granulosa cells, and this arrests the dormant oocytes in their quiescent states, leading to oocyte death. Overactivation of mTORC1 signaling in pfGCs accelerates the differentiation of pfGCs into granulosa cells and causes premature activation of all dormant oocytes and primordial follicles. We further show that pfGCs trigger the awakening of dormant oocytes through KIT ligand (KITL), and we present an essential communication network between the somatic cells and germ cells that is based on signaling between the mTORC1-KITL cascade in pfGCs and KIT-PI3K signaling in oocytes.
  
  
  CONCLUSIONS
  Our findings provide a relatively complete picture of how mammalian primordial follicles are activated. The microenvironment surrounding primordial follicles can activate mTORC1-KITL signaling in pfGCs, and these cells trigger the awakening of dormant oocytes and complete the process of follicular activation. Such communication between the microenvironment, somatic cells, and germ cells is essential to maintaining the proper reproductive lifespan in mammals.
authors.affiliation: Department of Chemistry and Molecular Biology, University of Gothenburg, 405 30 Gothenburg, Sweden.
authors.forename: Hua
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Department of Chemistry and Molecular Biology, University of Gothenburg, 405 30 Gothenburg, Sweden.
authors.forename: Sanjiv
authors.initials: S
authors.lastname: Risal
authors.affiliation: Department of Chemistry and Molecular Biology, University of Gothenburg, 405 30 Gothenburg, Sweden.
authors.forename: Nagaraju
authors.initials: N
authors.lastname: Gorre
authors.affiliation: Department of Chemistry and Molecular Biology, University of Gothenburg, 405 30 Gothenburg, Sweden.
authors.forename: Kiran
authors.initials: K
authors.lastname: Busayavalasa
authors.affiliation: Department of Chemistry and Molecular Biology, University of Gothenburg, 405 30 Gothenburg, Sweden.
authors.forename: Xin
authors.initials: X
authors.lastname: Li
authors.affiliation: Department of Chemistry and Molecular Biology, University of Gothenburg, 405 30 Gothenburg, Sweden.
authors.forename: Yan
authors.initials: Y
authors.lastname: Shen
authors.affiliation: Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Benedikt
authors.initials: B
authors.lastname: Bosbach
authors.affiliation: Department of Obstetrics and Gynecology, Sahlgrenska Academy, University of Gothenburg, 416 85 Gothenburg, Sweden.
authors.forename: Mats
authors.initials: M
authors.lastname: Brännström
authors.affiliation: Department of Chemistry and Molecular Biology, University of Gothenburg, 405 30 Gothenburg, Sweden. Electronic address: kui.liu@gu.se.
authors.forename: Kui
authors.initials: K
authors.lastname: Liu
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics; D000818:Animals; D005260:Female; D017353:Gene Deletion; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D008810:Mice, Inbred C57BL; D046912:Multiprotein Complexes / Q000378:metabolism; D009865:Oocytes / Q000254:growth & development*; D006080:Ovarian Follicle / Q000502:physiology*; D010766:Phosphorylation; D000076223:Regulatory-Associated Protein of mTOR; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D000077004:Tuberous Sclerosis Complex 1 Protein; D025521:Tumor Suppressor Proteins / Q000235:genetics
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D046912:Multiprotein Complexes; D000076223:Regulatory-Associated Protein of mTOR; C540162:Rptor protein, mouse; D000077004:Tuberous Sclerosis Complex 1 Protein; D025521:Tumor Suppressor Proteins; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases