title: Transcription factor genes Smad4 and Gata4 cooperatively regulate cardiac valve development. [corrected]
abstract: We report that the dominant human missense mutations G303E and G296S in GATA4, a cardiac-specific transcription factor gene, cause atrioventricular septal defects and valve abnormalities by disrupting a signaling cascade involved in endocardial cushion development. These GATA4 missense mutations, but not a mutation causing secundum atrial septal defects (S52F), demonstrated impaired protein interactions with SMAD4, a transcription factor required for canonical bone morphogenetic protein/transforming growth factor-β (BMP/TGF-β) signaling. Gata4 and Smad4 genetically interact in vivo: atrioventricular septal defects result from endothelial-specific Gata4 and Smad4 compound haploinsufficiency. Endothelial-specific knockout of Smad4 caused an absence of valve-forming activity: Smad4-deficient endocardium was associated with acellular endocardial cushions, absent epithelial-to-mesenchymal transformation, reduced endocardial proliferation, and loss of Id2 expression in valve-forming regions. We show that Gata4 and Smad4 cooperatively activated the Id2 promoter, that human GATA4 mutations abrogated this activity, and that Id2 deficiency in mice could cause atrioventricular septal defects. We suggest that one determinant of the phenotypic spectrum caused by human GATA4 mutations is differential effects on GATA4/SMAD4 interactions required for endocardial cushion development.
authors.affiliation: Department of Pediatrics, University of Chicago, Chicago, IL 60637, USA. imoskowitz@peds.bsd.uchicago.edu
authors.forename: Ivan P
authors.initials: IP
authors.lastname: Moskowitz
authors.forename: Jun
authors.initials: J
authors.lastname: Wang
authors.forename: Michael A
authors.initials: MA
authors.lastname: Peterson
authors.forename: William T
authors.initials: WT
authors.lastname: Pu
authors.forename: Alexander C
authors.initials: AC
authors.lastname: Mackinnon
authors.forename: Leif
authors.initials: L
authors.lastname: Oxburgh
authors.forename: Gerald C
authors.initials: GC
authors.lastname: Chu
authors.forename: Molly
authors.initials: M
authors.lastname: Sarkar
authors.forename: Charles
authors.initials: C
authors.lastname: Berul
authors.forename: Leslie
authors.initials: L
authors.lastname: Smoot
authors.forename: Elizabeth J
authors.initials: EJ
authors.lastname: Robertson
authors.forename: Robert
authors.initials: R
authors.lastname: Schwartz
authors.forename: Jonathan G
authors.initials: JG
authors.lastname: Seidman
authors.forename: Christine E
authors.initials: CE
authors.lastname: Seidman
mesh_terms: D000818:Animals; D019485:Bone Morphogenetic Proteins / Q000378:metabolism; D058750:Epithelial-Mesenchymal Transition; D005260:Female; D050991:GATA4 Transcription Factor / Q000235:genetics*; D006351:Heart Valves / Q000196:embryology*; D006801:Humans; D008297:Male; D051379:Mice; D009024:Morphogenesis; D009154:Mutation; D010375:Pedigree; D011401:Promoter Regions, Genetic; D051901:Smad4 Protein / Q000235:genetics*; D016212:Transforming Growth Factor beta / Q000378:metabolism
chemical_list: D019485:Bone Morphogenetic Proteins; D050991:GATA4 Transcription Factor; C484170:GATA4 protein, human; C484171:Gata4 protein, mouse; C497796:SMAD4 protein, human; D051901:Smad4 Protein; C490810:Smad4 protein, mouse; D016212:Transforming Growth Factor beta