title: GADD45G functions in male sex determination by promoting p38 signaling and Sry expression.
abstract: 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.
authors.affiliation: Institute of Molecular Biology, 55128 Mainz, Germany.
authors.forename: Mathias S
authors.initials: MS
authors.lastname: Gierl
authors.forename: Wolfram H
authors.initials: WH
authors.lastname: Gruhn
authors.forename: Annika
authors.initials: A
authors.lastname: von Seggern
authors.forename: Nicole
authors.initials: N
authors.lastname: Maltry
authors.forename: Christof
authors.initials: C
authors.lastname: Niehrs
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D019175:DNA Methylation; D005260:Female; D050991:GATA4 Transcription Factor / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D024282:Genes, sry; D006061:Gonadal Dysgenesis, 46,XY / Q000196:embryology / Q000235:genetics / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins; D020935:MAP Kinase Signaling System; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D008822:Mice, Transgenic; D055758:SOX9 Transcription Factor / Q000235:genetics / Q000378:metabolism; D019849:Sex Determination Processes / Q000235:genetics / Q000502:physiology*; D051876:Sex-Determining Region Y Protein / Q000235:genetics / Q000378:metabolism*; D013737:Testis / Q000196:embryology / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*; D000097642:GADD45 Proteins
chemical_list: D002352:Carrier Proteins; D050991:GATA4 Transcription Factor; D047908:Intracellular Signaling Peptides and Proteins; D055758:SOX9 Transcription Factor; D051876:Sex-Determining Region Y Protein; D048051:p38 Mitogen-Activated Protein Kinases; C121373:Gadd45g protein, mouse; D000097642:GADD45 Proteins; C484171:Gata4 protein, mouse; C527933:Sox9 protein, mouse; C497746:Sry protein, mouse