Combinatorial Expression of GATA4, Nkx2-5, and Serum Response Factor Directs Early Cardiac Gene Activity

Sepulveda, Jorge L.; Vlahopoulos, Spiros; Iyer, Dinakar; Belaguli, Narasimhaswamy S.; Schwartz, Robert J.

doi:10.1074/jbc.m203122200

Cited by 151 publications

(108 citation statements)

References 47 publications

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“…The constructions of Nkx2-5 promoter-driven luciferase reporter and Id2 promoter-driven luciferase reporter, respectively, were described (35,39,40). Bacterial and mammalian SMAD4 expression vectors were detailed previously (25).…”

Section: Methodsmentioning

confidence: 99%

Transcription factor genes Smad4 and Gata4 cooperatively regulate cardiac valve development

Moskowitz

Wang²,

Peterson³

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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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.

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Section: Methodsmentioning

confidence: 99%

Transcription factor genes Smad4 and Gata4 cooperatively regulate cardiac valve development

Moskowitz

Wang²,

Peterson³

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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“…Like these other cardiac regulatory genes, the function of Nkx2.5 is to regulate the expression of various molecular components of the myocardium (e.g., sarcomeric proteins, ion channels, etc. ), and it does so in combination with these other transcriptional factors (Chen and Schwartz, 1996;Black and Olson, 1998;Lee et al, 1998;Chen et al, 2002;Sepulveda et al, 2002). In other words, Nkx2.5 helps regulate the functional properties of the myocardium, but does not determine the properties of cardiac stem cells.…”

Section: The Molecular Phenotype Of Precardiac Stem Cellsmentioning

confidence: 99%

Stem cells and the formation of the myocardium in the vertebrate embryo

2003

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A major goal in cardiovascular biology is to repair diseased or damaged hearts with newly generated myocardial tissue. Stem cells offer a potential source of replacement myocytes for restoring cardiac function. Yet little is known about the nature of the cells that are able to generate myocardium and the conditions they require to form heart tissue. A source of information that may be pertinent to addressing these issues is the study of how the myocardium arises from progenitor cells in the early vertebrate embryo. Accordingly, this review will examine the initial events of cardiac developmental biology for insights into the identity and characteristics of the stem cells that can be used to generate myocardial tissue for therapeutic purposes. Anat Rec Part A 276A:2-12, 2004.

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“…For the most part, Ets factor-dependent ternary complexes do not play a role in regulating SRF-dependent myogenic gene targets. Instead, SRF co-accessory factor association with homeodomain factors like Nkx2-5 (20,21), zinc finger proteins like GATA4 (22), LIM factors like CRP2 (23), and myocardin (24) and its close relatives MRTFs and MAL (25,26) deliver powerful SRF-dependent muscle gene activity.…”

mentioning

confidence: 99%

Identification of Direct Serum-response Factor Gene Targets during Me2SO-induced P19 Cardiac Cell Differentiation

Zhang

Garcia-Gras

Wycuff

et al. 2005

Journal of Biological Chemistry

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Serum-response factor (SRF) is an obligatory transcription factor, required for the formation of vertebrate mesoderm leading to the origin of the cardiovascular system. Protein A-TEV-tagged chromatin immunoprecipitation technology was used to collect direct SRF-bound gene targets from pluripotent P19 cells, induced by Me 2 SO treatment into an enriched cardiac cell population. From 242 sequenced DNA fragments, we identified 188 genomic DNA fragments as potential direct SRF targets that contain CArG boxes and CArG-like boxes. Of the 92 contiguous genes that were identified, a subgroup of 43 SRF targets was then further validated by co-transfection assays with SRF. Expression patterns of representative candidate genes were compared with the LacZ reporter expression activity of the endogenous SRF gene. According to the Unigene data base, 84% of the SRF target candidates were expressed, at least, in the heart. In SRF null embryonic stem cells, 81% of these SRF target candidates were greatly affected by the absence of SRF. Among these SRF-regulated genes, Raf1, Map4k4, and Bicc1 have essential roles in mesoderm formation. The 12 regulated SRF target genes, Mapk10 (JNK3), Txnl2, Azi2, Tera, Sema3a, Lrp4, Actc1, Myl3, Hspg2, Pgm2, Hif3a, and Asb5, have been implicated in cardiovascular formation, and the Ski and Hes6 genes have roles in muscle differentiation. SRF target genes related to cell mitosis and cycle, E2f5, Npm1, Cenpb, Rbbp6, and Scyl1, expressed in the heart tissue were differentially regulated in SRF null ES cells.

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Combinatorial Expression of GATA4, Nkx2-5, and Serum Response Factor Directs Early Cardiac Gene Activity

Cited by 151 publications

References 47 publications

Transcription factor genes Smad4 and Gata4 cooperatively regulate cardiac valve development

Transcription factor genes Smad4 and Gata4 cooperatively regulate cardiac valve development

Stem cells and the formation of the myocardium in the vertebrate embryo

Identification of Direct Serum-response Factor Gene Targets during Me2SO-induced P19 Cardiac Cell Differentiation

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