title: Bone morphogenetic protein 4 promotes mammalian oogonial stem cell differentiation via Smad1/5/8 signaling.
abstract: OBJECTIVE
  To test whether bone morphogenetic protein 4 (BMP4) directly regulates differentiation of adult mouse ovary-derived oogonial stem cells (OSCs) in vitro.
  
  
  METHODS
  Animal study.
  
  
  METHODS
  Research laboratory.
  
  
  METHODS
  Adult C57BL/6 female mice.
  
  
  METHODS
  After purification from adult ovaries by fluorescence-activated cell sorting, OSCs were cultured without or with BMP4 in the absence or presence of the BMP4 antagonist, Noggin.
  
  
  METHODS
  Rates of in vitro-derived (IVD) oocyte formation and changes in gene expression were assessed.
  
  
  RESULTS
  Cultured OSCs expressed BMP receptor (BMPR) 1A (BMPR1A), BMPR1B, and BMPR2, suggesting that BMP signaling can directly affect OSC function. In agreement with this, BMP4 significantly increased the number of IVD oocytes formed by cultured OSCs in a dose-dependent manner, and this response was inhibited in a dose-dependent fashion by cotreatment with Noggin. Exposure of OSCs to BMP4 was associated with rapid phosphorylation of BMPR-regulated Smad1/5/8 proteins, and this response was followed by increased expression of the meiosis initiation factors, stimulated by retinoic acid gene 8 (Stra8), muscle-segment homeobox 1 (Msx1), and Msx2. In keeping with the IVD oocyte formation data, the ability of BMP4 to activate Smad1/5/8 signaling and meiotic gene expression in OSCs was abolished by cotreatment with Noggin.
  
  
  CONCLUSIONS
  Engagement of BMP4-mediated signaling in adult mouse ovary-derived OSCs cultured in vitro drives differentiation of these cells into IVD oocytes through Smad1/5/8 activation and transcriptional up-regulation of key meiosis-initiating genes.
authors.affiliation: Vincent Center for Reproductive Biology, Massachusetts General Hospital, and Department of Obstetrics, Gynecology and Reproductive Biology, Harvard Medical School, Boston, Massachusetts.
authors.forename: Eun-Sil
authors.initials: ES
authors.lastname: Park
authors.forename: Dori C
authors.initials: DC
authors.lastname: Woods
authors.forename: Jonathan L
authors.initials: JL
authors.lastname: Tilly
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D053687:Adult Stem Cells / Q000187:drug effects* / Q000378:metabolism; D000818:Animals; D055415:Bone Morphogenetic Protein 4 / Q000494:pharmacology*; D052004:Bone Morphogenetic Protein Receptors / Q000235:genetics / Q000378:metabolism; D002352:Carrier Proteins / Q000494:pharmacology; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D005260:Female; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D051957:MSX1 Transcription Factor / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009865:Oocytes / Q000187:drug effects* / Q000378:metabolism; D009866:Oogenesis / Q000187:drug effects*; D010766:Phosphorylation; D011994:Recombinant Proteins / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects*; D051898:Smad1 Protein / Q000378:metabolism*; D051902:Smad5 Protein / Q000378:metabolism*; D051904:Smad8 Protein / Q000378:metabolism*; D013997:Time Factors; D000099176:Noggin Protein
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D055415:Bone Morphogenetic Protein 4; D052004:Bone Morphogenetic Protein Receptors; D002352:Carrier Proteins; D018398:Homeodomain Proteins; D051957:MSX1 Transcription Factor; D011994:Recombinant Proteins; D051898:Smad1 Protein; D051902:Smad5 Protein; D051904:Smad8 Protein; D000099176:Noggin Protein; C525809:BMP4 protein, human; C084119:MSX2 protein; C484084:Msx1 protein, mouse; C497401:Smad1 protein, mouse; C497798:Smad5 protein, mouse; C491621:Smad9 protein, mouse; C102019:Stra8 protein, mouse
keywords: BMP4; germ cells; oocyte; oogenesis; stem cells