GATA4 is a dosage-sensitive regulator of cardiac morphogenesis

Pu, William T.; Ishiwata, Takahiro; Juraszek, Amy L.; Ma, Qing; Izumo, Seigo

doi:10.1016/j.ydbio.2004.08.008

Cited by 199 publications

(190 citation statements)

References 30 publications

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“…In this study, we used mice on a uniform genetic background that were heterozygous for deletion of the second exon of Gata4 (Gata4 WT/⌬ex2 , abbreviated G4D), including the start codon and the N-terminal 46% of the coding region (11). To confirm reduction in Gata4 expression, we performed quantitative real-time RT-PCR (qRT-PCR) and Western blotting on ventricular samples and found that Gata4 mRNA and protein were reduced in G4D mice by 52 Ϯ 5% and by 58 Ϯ 4%, respectively, compared with wild-type littermate controls (WT; P Ͻ 0.05; Fig.…”

Section: Resultsmentioning

confidence: 99%

“…By direct measurement, we determined that cardiomyocyte number was reduced to a similar degree (24% reduction) in fetal G4D hearts. Reduced Gata4 dosage in fetal cardiomyocytes resulted in decreased cardiomyocyte proliferation (10,11). Gata4 also promotes cardiomyocyte differentiation from progenitor cells (23).…”

Section: Gata4 Regulation Of Cardiomyocyte Hypertrophy Based On In Vmentioning

confidence: 99%

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Gata4 is required for maintenance of postnatal cardiac function and protection from pressure overload-induced heart failure

Bisping

Ikeda

Kong

et al. 2006

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

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An important event in the pathogenesis of heart failure is the development of pathological cardiac hypertrophy. In cultured cardiomyocytes, the transcription factor Gata4 is required for agonist-induced hypertrophy. We hypothesized that, in the intact organism, Gata4 is an important regulator of postnatal heart function and of the hypertrophic response of the heart to pathological stress. To test this hypothesis, we studied mice heterozygous for deletion of the second exon of Gata4 (G4D). At baseline, G4D mice had mild systolic and diastolic dysfunction associated with reduced heart weight and decreased cardiomyocyte number. After transverse aortic constriction (TAC), G4D mice developed overt heart failure and eccentric cardiac hypertrophy, associated with significantly increased fibrosis and cardiomyocyte apoptosis. Inhibition of apoptosis by overexpression of the insulin-like growth factor 1 receptor prevented TAC-induced heart failure in G4D mice. Unlike WT-TAC controls, G4D-TAC cardiomyocytes hypertrophied by increasing in length more than width. Gene expression profiling revealed up-regulation of genes associated with apoptosis and fibrosis, including members of the TGF-␤ pathway. Our data demonstrate that Gata4 is essential for cardiac function in the postnatal heart. After pressure overload, Gata4 regulates the pattern of cardiomyocyte hypertrophy and protects the heart from load-induced failure.apoptosis ͉ hypertrophy ͉ fibrosis ͉ gene expression ͉ Igf-1 H eart failure is one of the leading causes of morbidity and mortality in industrialized countries (1). An important event in the pathogenesis of heart failure is the development of pathological cardiac hypertrophy (2). This is characterized by increased cardiomyocyte size, increased protein synthesis, and altered gene expression. Over time, the changes in gene expression can be maladaptive and contribute to progression of heart failure (3).A large body of evidence suggests that the transcription factor Gata4 is an important regulator of cardiomyocyte hypertrophy (4, 5). Gata4 has been implicated in the regulation of an array of cardiac genes in response to hypertrophic agonists, including atrial natriuretic factor (ANF), brain natriuretic peptide (BNP), skeletal ␣-actin, ␣-myosin heavy chain (␣-MHC), and ␤-myosin heavy chain (␤-MHC) (4, 5). Gata4 overexpression is sufficient to induce the hypertrophic response in cultured neonatal cardiomyocytes and transgenic mice (6). Moreover, the hypertrophic response of cultured neonatal rat cardiomyocytes requires Gata4 (6, 7).We sought to investigate the in vivo role of Gata4 in regulating postnatal heart function and the response to hypertrophic stress. Traditional loss-of-function approaches have been complicated by early embryonic lethality in Gata4 null embryos (8, 9). In our hands, embryos with embryonic cardiac-restricted Gata4 inactivation also suffered from fetal demise (10). These embryos died from heart failure, and the mutant hearts were characterized by marked myocardial hypoplasia due to decreased ca...

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Section: Resultsmentioning

confidence: 99%

Section: Gata4 Regulation Of Cardiomyocyte Hypertrophy Based On In Vmentioning

confidence: 99%

Gata4 is required for maintenance of postnatal cardiac function and protection from pressure overload-induced heart failure

Bisping

Ikeda

Kong

et al. 2006

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

Self Cite

173

149

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“…In this context, GATA-4 acts as an integrator of two signaling pathways: PKC, which targets its C-terminal domain, resulting in enhanced DNA binding activity, and the JAK-STAT pathway, which potentiates its activity through protein-protein interaction with STATs. GATA-4, a member of the GATA family of tissue-specific zinc finger proteins, is a critical regulator of cardiogenesis (26,58). In postnatal cardiomyocytes, GATA-4 is essential for maintaining the cardiac genetic program (14) and for the adaptive response of the heart to numerous stimuli, including hormones and work overload (15,42,57).…”

Section: Discussionmentioning

confidence: 99%

Convergence of Protein Kinase C and JAK-STAT Signaling on Transcription Factor GATA-4

Wang

Paradis

Aries

et al. 2005

Molecular and Cellular Biology

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Angiotensin II (AII), a potent vasoactive hormone, acts on numerous organs via G-protein-coupled receptors and elicits cell-specific responses. At the level of the heart, AII stimulation alters gene transcription and leads to cardiomyocyte hypertrophy. Numerous intracellular signaling pathways are activated in this process; however, which of these directly link receptor activation to transcriptional regulation remains undefined. We used the atrial natriuretic factor (ANF) gene (NPPA) as a marker to elucidate the signaling cascades involved in AII transcriptional responses. We show that ANF transcription is activated directly by the AII type 1 receptor and precedes the development of myocyte hypertrophy. This response maps to STAT and GATA binding sites, and the two elements transcriptionally cooperate to mediate signaling through the JAK-STAT and protein kinase C (PKC)-GATA-4 pathways. PKC phosphorylation enhances GATA-4 DNA binding activity, and STAT-1 functionally and physically interacts with GATA-4 to synergistically activate AII and other growth factor-inducible promoters. Moreover, GATA factors are able to recruit STAT proteins to target promoters via GATA binding sites, which are sufficient to support synergy. Thus, STAT proteins can act as growth factor-inducible coactivators of tissue-specific transcription factors. Interactions between STAT and GATA proteins may provide a general paradigm for understanding cell specificity of cytokine and growth factor signaling.

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“…The phenotype of zebrafish gata5 mutants closely resembles the cardiac phenotypes in gata4 mutant mice. Myocardium-restricted deletion of murine gata4 or gata4/gata6 double heterozygote causes a marked reduction in cardiomyocyte proliferation and results in hypoplastic hearts (5)(6)(7). Although it seems to be clear that certain levels of GATA activity are required to drive myocardial proliferative growth, opposing signals might also be necessary to constrain the excessive cardiac growth during development.…”

mentioning

confidence: 99%

Vertebrate heart growth is regulated by functional antagonism between Gridlock and Gata5

Jia

King²,

Chopra³

et al. 2007

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

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Embryonic organs attain their final dimensions through the generation of proper cell number and size, but the control mechanisms remain obscure. Here, we establish Gridlock (Grl), a Hairy-related basic helix-loop-helix (bHLH) transcription factor, as a negative regulator of cardiomyocyte proliferative growth in zebrafish embryos. Mutations in grl cause an increase in expression of a group of immediate-early growth genes, myocardial genes, and development of hyperplastic hearts. Conversely, cardiomyocytes with augmented Grl activity have diminished cell volume and fail to divide, resulting in a marked reduction in heart size. Both bHLH domain and carboxyl region are required for Grl negative control of myocardial proliferative growth. These Grl-induced cardiac effects are counterbalanced by the transcriptional activator Gata5 but not Gata4, which promotes cardiomyocyte expansion in the embryo. Biochemical analyses show that Grl forms a complex with Gata5 through the carboxyl region and can repress Gata5-mediated transcription via the bHLH domain. Hence, our studies suggest that Grl regulates embryonic heart growth via opposing Gata5, at least in part through their protein interactions in modulating gene expression.cardiomyocyte ͉ proliferation ͉ size control ͉ transcription T he embryonic heart grows through a combination of cardiomyocyte proliferation and an increase in cell mass due to the generation of myofibrillar arrays (1). Cardiac proliferation diminishes progressively after birth, and postmitotic hypertrophy in the adult heart provides most of the adaptive responses necessary to supply increased cardiac output (2). Despite recent progress that has been made in the regulation of postnatal cardiac hypertrophy, the mechanisms and pathways that control embryonic heart growth are poorly delineated. It is not known what molecular signals restrain cardiomyocyte proliferative growth in the embryonic heart. The GATA zinc-finger transcription factors promote myocardial differentiation and expansion. Among the three gata genes (gata4, gata5, and gata6) in zebrafish, gata5 plays the most prominent role in heart growth and development (3). Mutations in gata5 in zebrafish cause a reduction in expression of early and late myocardial genes and a decrease in cardiac progenitor cells and proliferative cardiomyocytes, resulting in small hearts. Forced gata5 expression in the zebrafish embryo increases heart size and occasionally produces ectopically beating myocardial tissue (4). The phenotype of zebrafish gata5 mutants closely resembles the cardiac phenotypes in gata4 mutant mice. Myocardium-restricted deletion of murine gata4 or gata4/gata6 double heterozygote causes a marked reduction in cardiomyocyte proliferation and results in hypoplastic hearts (5-7). Although it seems to be clear that certain levels of GATA activity are required to drive myocardial proliferative growth, opposing signals might also be necessary to constrain the excessive cardiac growth during development.grl encodes a hairy-related basic helix-loop-h...

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GATA4 is a dosage-sensitive regulator of cardiac morphogenesis

Cited by 199 publications

References 30 publications

Gata4 is required for maintenance of postnatal cardiac function and protection from pressure overload-induced heart failure

Gata4 is required for maintenance of postnatal cardiac function and protection from pressure overload-induced heart failure

Convergence of Protein Kinase C and JAK-STAT Signaling on Transcription Factor GATA-4

Vertebrate heart growth is regulated by functional antagonism between Gridlock and Gata5

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