title: Gadd45γ and Map3k4 interactions regulate mouse testis determination via p38 MAPK-mediated control of Sry expression.
abstract: Loss of the kinase MAP3K4 causes mouse embryonic gonadal sex reversal due to reduced expression of the testis-determining gene, Sry. However, because of widespread expression of MAP3K4, the cellular basis of this misregulation was unclear. Here, we show that mice lacking Gadd45γ also exhibit XY gonadal sex reversal caused by disruption to Sry expression. Gadd45γ is expressed in a dynamic fashion in somatic cells of the developing gonads from 10.5 days postcoitum (dpc) to 12.5 dpc. Gadd45γ and Map3k4 genetically interact during sex determination, and transgenic overexpression of Map3k4 rescues gonadal defects in Gadd45γ-deficient embryos. Sex reversal in both mutants is associated with reduced phosphorylation of p38 MAPK and GATA4. In addition, embryos lacking both p38α and p38β also exhibit XY gonadal sex reversal. Taken together, our data suggest a requirement for GADD45γ in promoting MAP3K4-mediated activation of p38 MAPK signaling in embryonic gonadal somatic cells for testis determination in the mouse.
authors.affiliation: Mammalian Genetics Unit, Medical Research Council, Harwell, Oxfordshire OX11 0RD, UK.
authors.forename: Nick
authors.initials: N
authors.lastname: Warr
authors.forename: Gwenn-Aël
authors.initials: GA
authors.lastname: Carre
authors.forename: Pam
authors.initials: P
authors.lastname: Siggers
authors.forename: Jessica Vitos
authors.initials: JV
authors.lastname: Faleato
authors.forename: Rachel
authors.initials: R
authors.lastname: Brixey
authors.forename: Madeleine
authors.initials: M
authors.lastname: Pope
authors.forename: Debora
authors.initials: D
authors.lastname: Bogani
authors.forename: Melissa
authors.initials: M
authors.lastname: Childers
authors.forename: Sara
authors.initials: S
authors.lastname: Wells
authors.forename: Cheryl L
authors.initials: CL
authors.lastname: Scudamore
authors.forename: Marianna
authors.initials: M
authors.lastname: Tedesco
authors.forename: Ivan
authors.initials: I
authors.lastname: del Barco Barrantes
authors.forename: Angel R
authors.initials: AR
authors.lastname: Nebreda
authors.forename: Paul A
authors.initials: PA
authors.lastname: Trainor
authors.forename: Andy
authors.initials: A
authors.lastname: Greenfield
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; D048768:MAP Kinase Kinase Kinase 4 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D020935:MAP Kinase Signaling System; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D048290:Mitogen-Activated Protein Kinase 11 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D048308:Mitogen-Activated Protein Kinase 14 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D008954:Models, Biological; D019849:Sex Determination Processes / Q000235:genetics / Q000502:physiology; D051876:Sex-Determining Region Y Protein / Q000235:genetics*; D013737:Testis / Q000196:embryology* / Q000378:metabolism*; D000097642:GADD45 Proteins
chemical_list: D002352:Carrier Proteins; D050991:GATA4 Transcription Factor; D047908:Intracellular Signaling Peptides and Proteins; D048768:MAP Kinase Kinase Kinase 4; D048290:Mitogen-Activated Protein Kinase 11; D048308:Mitogen-Activated Protein Kinase 14; D051876:Sex-Determining Region Y Protein; C121373:Gadd45g protein, mouse; D000097642:GADD45 Proteins; C484171:Gata4 protein, mouse; C497746:Sry protein, mouse; C482780:Map3k4 protein, mouse