Gadd45γ and Map3k4 Interactions Regulate Mouse Testis Determination via p38 MAPK-Mediated Control of Sry Expression

• Published in: Developmental cell 2012-11, Vol.23 (5), p.1020-1031
• Main Authors: Warr, Nick, Carre, Gwenn-Aël, Siggers, Pam, Faleato, Jessica Vitos, Brixey, Rachel, Pope, Madeleine, Bogani, Debora, Childers, Melissa, Wells, Sara, Scudamore, Cheryl L., Tedesco, Marianna, del Barco Barrantes, Ivan, Nebreda, Angel R., Trainor, Paul A., Greenfield, Andy
• Format: Article
• Language: English
• Subjects: Animals; Biological and medical sciences; Carrier Proteins - genetics; Carrier Proteins - metabolism; Cell differentiation, maturation, development, hematopoiesis; Cell physiology; DNA Methylation; Female; Fundamental and applied biological sciences. Psychology; 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; Male; MAP Kinase Kinase Kinase 4 - deficiency; MAP Kinase Kinase Kinase 4 - genetics; MAP Kinase Kinase Kinase 4 - metabolism; MAP Kinase Signaling System; Mice; Mice, Inbred C57BL; Mice, Knockout; Mitogen-Activated Protein Kinase 11 - deficiency; Mitogen-Activated Protein Kinase 11 - genetics; Mitogen-Activated Protein Kinase 11 - metabolism; Mitogen-Activated Protein Kinase 14 - deficiency; Mitogen-Activated Protein Kinase 14 - genetics; Mitogen-Activated Protein Kinase 14 - metabolism; Models, Biological; Molecular and cellular biology; Sex Determination Processes - genetics; Sex Determination Processes - physiology; Sex-Determining Region Y Protein - genetics; Testis - embryology; Testis - metabolism
• ISSN: 1534-5807; 1878-1551
• DOI: 10.1016/j.devcel.2012.09.016

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. [Display omitted] ► Loss of Gadd45γ disrupts Sry expression and causes XY gonadal sex reversal ► Gadd45γ interacts with Map3k4 during testis determination ► Loss of Gadd45γ and Map3k4 disrupts p38 MAPK signaling and GATA4 phosphorylation ► Double-knockout embryos lacking p38α and p38β exhibit XY gonadal sex reversal Testis determination in mammals is initiated by Sry expression. Warr et al. report XY gonadal sex reversal in mice lacking GADD45γ, a protein associated with cellular stress. Genetic and biochemical studies suggest a molecular pathway, linking GADD45γ, MAP3K4, p38 MAPK, and GATA4, required for the proper regulation of Sry expression.