title: Lhx8 regulates primordial follicle activation and postnatal folliculogenesis.
abstract: BACKGROUND
  The early stages of ovarian follicle formation-beginning with the breakdown of germ cell cysts and continuing with the formation of primordial follicles and transition to primary and secondary follicles-are critical in determining reproductive life span and fertility. Previously, we discovered that global knockouts of germ cell-specific transcriptional co-regulators Sohlh1, Sohlh2, Lhx8, and Nobox, cause rapid oocyte loss and ovarian failure. Also factors such as Nobox and Sohlh1 are associated with human premature ovarian failure. In this study, we developed a conditional knockout of Lhx8 to study oocyte-specific pathways in postnatal folliculogenesis.
  
  
  RESULTS
  The conditional deficiency of Lhx8 in the oocytes of primordial follicles leads to massive primordial oocyte activation, in part, by indirectly interacting with the PI3K-AKT pathway, as shown by synergistic effects on FOXO3 nucleocytoplasmic translocation and rpS6 activation. However, LHX8 does not directly regulate members of the PI3K-AKT pathway; instead, we show that LHX8 represses Lin28a expression, a known regulator of mammalian metabolism and of the AKT/mTOR pathway. LHX8 can bind to the Lin28a promoter, and the depletion of Lin28a in Lhx8-deficient oocytes partially suppresses primordial oocyte activation. Moreover, unlike the PI3K-AKT pathway, LHX8 is critical beyond primordial follicle activation, and blocks the primary to secondary follicle transition.
  
  
  CONCLUSIONS
  Our results indicate that the LHX8-LIN28A pathway is essential in the earliest stages of primordial follicle activation, and LHX8 is an important oocyte-specific transcription factor in the ovary for regulating postnatal folliculogenesis.
authors.affiliation: Magee-Womens Research Institute, Department of Obstetrics, Gynecology and Reproductive Sciences, University of Pittsburgh, Pittsburgh, PA, 15213, USA. yur4@pitt.edu.
authors.forename: Yu
authors.initials: Y
authors.lastname: Ren
authors.affiliation: Magee-Womens Research Institute, Department of Obstetrics, Gynecology and Reproductive Sciences, University of Pittsburgh, Pittsburgh, PA, 15213, USA. suzukih.arc@cmn.tmd.ac.jp.|Department of Experimental Animal Model for Human Disease, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo, 113-8510, Japan. suzukih.arc@cmn.tmd.ac.jp.
authors.forename: Hitomi
authors.initials: H
authors.lastname: Suzuki
authors.affiliation: Magee-Womens Research Institute, Department of Obstetrics, Gynecology and Reproductive Sciences, University of Pittsburgh, Pittsburgh, PA, 15213, USA. Jagarlamudikr@mwri.magee.edu.|Department of Pathology, University of Pittsburgh, Pittsburgh, PA, 15213, USA. Jagarlamudikr@mwri.magee.edu.
authors.forename: Krishna
authors.initials: K
authors.lastname: Jagarlamudi
authors.affiliation: Magee-Womens Research Institute, Department of Obstetrics, Gynecology and Reproductive Sciences, University of Pittsburgh, Pittsburgh, PA, 15213, USA. mcgeekj@mwri.magee.edu.
authors.forename: Kayla
authors.initials: K
authors.lastname: Golnoski
authors.affiliation: Magee-Womens Research Institute, Department of Obstetrics, Gynecology and Reproductive Sciences, University of Pittsburgh, Pittsburgh, PA, 15213, USA. mmcguire887@gmail.com.
authors.forename: Megan
authors.initials: M
authors.lastname: McGuire
authors.affiliation: Division of Molecular Neurobiology, MRC National Institute of Medical Research, London, NW7 1AA, UK. rlopes@nimr.mrc.ac.uk.
authors.forename: Rita
authors.initials: R
authors.lastname: Lopes
authors.affiliation: Division of Molecular Neurobiology, MRC National Institute of Medical Research, London, NW7 1AA, UK. vpachni@nimr.mrc.ac.uk.
authors.forename: Vassilis
authors.initials: V
authors.lastname: Pachnis
authors.affiliation: Magee-Womens Research Institute, Department of Obstetrics, Gynecology and Reproductive Sciences, University of Pittsburgh, Pittsburgh, PA, 15213, USA. rajkovic@upmc.edu.|Department of Pathology, University of Pittsburgh, Pittsburgh, PA, 15213, USA. rajkovic@upmc.edu.|Department of Human Genetics, University of Pittsburgh, Pittsburgh, PA, 15213, USA. rajkovic@upmc.edu.
authors.forename: Aleksandar
authors.initials: A
authors.lastname: Rajkovic
mesh_terms: D000818:Animals; D005260:Female; D060850:LIM-Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009865:Oocytes / Q000166:cytology* / Q000378:metabolism; D006080:Ovarian Follicle / Q000502:physiology* / Q000648:ultrastructure*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011401:Promoter Regions, Genetic; D060066:Protein Interaction Maps; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: C112960:LIM homeobox protein 8; D060850:LIM-Homeodomain Proteins; C488352:Lin-28 protein, mouse; D016601:RNA-Binding Proteins; D014157:Transcription Factors; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt