Smad2 and p38 signaling pathways act in concert to determine xy primordial germ cell fate in mice

Quan Wu, Kurumi Fukuda, Michael Weinstein, Jonathan M. Graff, Yumiko Saga

Research output: Contribution to journalArticlepeer-review

24 Scopus citations


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 XYPGCs ledto a loss ofmale-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.

Original languageEnglish (US)
Pages (from-to)575-586
Number of pages12
JournalDevelopment (Cambridge)
Issue number3
StatePublished - Feb 1 2015


  • Meiosis
  • Nanos2
  • P38 signaling
  • SMAD2 signaling
  • Sex determination
  • Smad2/3 conditional knockout mice

ASJC Scopus subject areas

  • Molecular Biology
  • Developmental Biology


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