title: SMAD2 and p38 signaling pathways act in concert to determine XY primordial germ cell fate in mice.
abstract: The sex of primordial germ cells (PGCs) is determined in developing gonads on the basis of cues from somatic cells. In XY gonads, sex-determining region Y (SRY) triggers fibroblast growth factor 9 (FGF9) expression in somatic cells. FGF signaling, together with downstream nodal/activin signaling, promotes male differentiation in XY germ cells by suppressing retinoic acid (RA)-dependent meiotic entry and inducing male-specific genes. However, the mechanism by which nodal/activin signaling regulates XY PGC fate is unknown. We uncovered the roles of SMAD2/3 and p38 MAPK, the putative downstream factors of nodal/activin signaling, in PGC sexual fate decision. We found that conditional deletion of Smad2, but not Smad3, from XY PGCs led to a loss of male-specific gene expression. Moreover, suppression of RA signaling did not rescue male-specific gene expression in Smad2-mutant testes, indicating that SMAD2 signaling promotes male differentiation in a RA-independent manner. By contrast, we found that p38 signaling has an important role in the suppression of RA signaling. The Smad2 deletion did not disrupt the p38 signaling pathway even though Nodal expression was significantly reduced, suggesting that p38 was not regulated by nodal signaling in XY PGCs. Additionally, the inhibition of p38 signaling in the Smad2-mutant testes severely impeded XY PGC differentiation and induced meiosis. In conclusion, we propose a model in which p38 and SMAD2 signaling coordinate to determine the sexual fate of XY PGCs.
authors.affiliation: Department of Genetics, SOKENDAI, Yata 1111, Mishima 411-8540, Japan Division of Mammalian Development, National Institute of Genetics, Yata 1111, Mishima 411-8540, Japan.
authors.forename: Quan
authors.initials: Q
authors.lastname: Wu
authors.affiliation: Department of Genetics, SOKENDAI, Yata 1111, Mishima 411-8540, Japan Division of Mammalian Development, National Institute of Genetics, Yata 1111, Mishima 411-8540, Japan.
authors.forename: Kurumi
authors.initials: K
authors.lastname: Fukuda
authors.affiliation: Department of Molecular Genetics and Division of Human Cancer Genetics, Ohio State University, 484 W. 12th Avenue, Columbus, OH 43210, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Weinstein
authors.affiliation: Department of Molecular Biology, University of Texas Southwestern Medical Center, 6000 Harry Hines Boulevard, NB5.118, Dallas, TX 75390, USA.
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Graff
authors.affiliation: Department of Genetics, SOKENDAI, Yata 1111, Mishima 411-8540, Japan Division of Mammalian Development, National Institute of Genetics, Yata 1111, Mishima 411-8540, Japan ysaga@nig.ac.jp.
authors.forename: Yumiko
authors.initials: Y
authors.lastname: Saga
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D015153:Blotting, Western; D002454:Cell Differentiation / Q000502:physiology*; D017931:DNA Primers / Q000235:genetics; D018507:Gene Expression Regulation, Developmental / Q000235:genetics / Q000502:physiology*; D007091:Image Processing, Computer-Assisted; D017403:In Situ Hybridization; D028322:Inhibin-beta Subunits / Q000378:metabolism; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D018613:Microscopy, Confocal; D008954:Models, Biological; D055457:Nodal Protein / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology*; D051899:Smad2 Protein / Q000378:metabolism*; D013094:Spermatozoa / Q000502:physiology*; D014212:Tretinoin / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
chemical_list: D017931:DNA Primers; D055457:Nodal Protein; C526008:Nodal protein, mouse; D051899:Smad2 Protein; C497783:Smad2 protein, mouse; C103008:inhibin beta A subunit; D014212:Tretinoin; D028322:Inhibin-beta Subunits; D048051:p38 Mitogen-Activated Protein Kinases
keywords: Meiosis; Nanos2; SMAD2 signaling; Sex determination; Smad2/3 conditional knockout mice; p38 signaling