GADD45G functions in male sex determination by promoting p38 signaling and Sry expression

Dev Cell. 2012 Nov 13;23(5):1032-42. doi: 10.1016/j.devcel.2012.09.014. Epub 2012 Oct 25.


Male sex determination in mammals is induced by Sry, a gene whose regulation is poorly understood. Here we show that mice mutant for the stress-response gene Gadd45g display complete male-to-female sex reversal. Gadd45g and Sry have a strikingly similar expression pattern in the genital ridge, and they are coexpressed in gonadal somatic cells. In Gadd45g mutants, Sry expression is delayed and reduced, and yet Sry seemed to remain poised for expression, because its promoter is demethylated on schedule and is occupied by active histone marks. Instead, p38 MAPK signaling is impaired in Gadd45g mutants. Moreover, the transcription factor GATA4, which is required for Sry expression, binds to the Sry promoter in vivo in a MAPK-dependent manner. The results suggest that a signaling cascade, involving GADD45G → p38 MAPK → GATA4 → SRY, regulates male sex determination.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Carrier Proteins / genetics
  • Carrier Proteins / metabolism*
  • DNA Methylation
  • Female
  • GATA4 Transcription Factor / metabolism
  • Gene Expression Regulation, Developmental
  • Genes, sry
  • Gonadal Dysgenesis, 46,XY / embryology
  • Gonadal Dysgenesis, 46,XY / genetics
  • Gonadal Dysgenesis, 46,XY / metabolism
  • Intracellular Signaling Peptides and Proteins
  • MAP Kinase Signaling System
  • Male
  • Mice
  • Mice, Mutant Strains
  • Mice, Transgenic
  • SOX9 Transcription Factor / genetics
  • SOX9 Transcription Factor / metabolism
  • Sex Determination Processes / genetics
  • Sex Determination Processes / physiology*
  • Sex-Determining Region Y Protein / genetics
  • Sex-Determining Region Y Protein / metabolism*
  • Testis / embryology
  • Testis / metabolism
  • p38 Mitogen-Activated Protein Kinases / metabolism*


  • Carrier Proteins
  • GATA4 Transcription Factor
  • Gadd45g protein, mouse
  • Gata4 protein, mouse
  • Intracellular Signaling Peptides and Proteins
  • SOX9 Transcription Factor
  • Sex-Determining Region Y Protein
  • Sox9 protein, mouse
  • Sry protein, mouse
  • p38 Mitogen-Activated Protein Kinases