Disease relevance of Gata4

• p204 is required for the differentiation of P19 murine embryonal carcinoma cells to beating cardiac myocytes: its expression is activated by the cardiac Gata4, Nkx2.5, and Tbx5 proteins [1].
• More provocatively, Gata4-deleted mice were compromised in their ability to hypertrophy following pressure overload or exercise stimulation [2].
• Adrenocortical tumorigenesis in transgenic mice expressing the inhibin alpha-subunit promoter/simian virus 40 T-antigen transgene: relationship between ectopic expression of luteinizing hormone receptor and transcription factor GATA-4 [3].
• Transcription factor GATA-4 is a marker of anaplasia in adrenocortical neoplasms of the domestic ferret (Mustela putorius furo) [4].
• Transcription factor GATA-4 plays critical roles in controlling heart development and cardiac hypertrophy [5].

High impact information on Gata4

• Zfpm2 interacts specifically with the N-terminal zinc finger of Gata4 and represses Gata4-dependent transcription [6].
• Gata4 is a zinc-finger transcription factor with a role in early cardiac development [6].
• Requirement of the transcription factor GATA4 for heart tube formation and ventral morphogenesis [7].
• Late deletion of Gata4 by Cre recombinase driven by the alpha myosin heavy chain promoter did not selectively affect RV development or generation of endocardial cushion mesenchyme but did result in marked myocardial thinning with decreased cardiomyocyte proliferation, as well as double-outlet RV [8].
• In order to circumvent the early embryonic lethality of Gata4-null embryos and to investigate the role of myocardial Gata4 expression in cardiac development, we used Cre/loxP technology to conditionally delete Gata4 in the myocardium of mice at an early and a late time point in cardiac morphogenesis [8].

Biological context of Gata4

• Similarities in the phenotypes of Gata4(-/-) chimeras and mice with other genetically engineered mutations that affect gut development suggest that GATA-4 may be involved in the gastric epithelial response to members of the TGF-beta superfamily [9].
• Our results demonstrate a general role of myocardial Gata4 in regulating cardiomyocyte proliferation and a specific, stage-dependent role in regulating the morphogenesis of the RV and the atrioventricular canal [8].
• To test the hypothesis that the regional expression of Gata4 is critical for the maintenance of jejunal-ileal homeostasis in the adult small intestine in vivo, we established an inducible, intestine-specific model that results in the synthesis of a transcriptionally inactive Gata4 mutant [10].
• Here, we define the regulation of a distal enhancer element from Gata4 that is sufficient to direct expression throughout the lateral mesoderm, beginning at 7.5 days of mouse embryonic development [11].
• Furthermore, ectopic p204 triggered the expression of Gata4 and Nkx2.5 in P19 cells. p204 contains a nuclear export signal and was partially translocated to the cytoplasm during the differentiation. p204 from which the nuclear export signal was deleted was not translocated, and it did not induce differentiation [1].

Anatomical context of Gata4

• Mouse fetuses homozygous for a null allele of Fog2 or homozygous for a targeted mutation in Gata4 (Gata4(ki)) that abrogates the interaction of GATA4 with FOG co-factors exhibit abnormalities in gonadogenesis [12].
• In situ hybridization analysis showed that Sox7 is co-expressed with Fgf-3 and Gata4 in the parietal endoderm of E7.5 mouse embryos [13].
• However, by E18.5, only rare patches of Gata4(-/-) epithelium were evident in the distal stomach [9].
• To explore the role of GATA-4 in specification of definitive gastric endoderm, we generated chimeric mice by introducing Gata4(-/-) ES cells into ROSA26 morulae or blastocysts [9].
• Morphogenesis of the right ventricle requires myocardial expression of Gata4 [8].

Associations of Gata4 with chemical compounds

• In an attempt to elucidate the role of GATA-4 in the formation of visceral endoderm, we have now differentiated Gata4 -/- and wild type embryoid bodies in the presence of retinoic acid +/- dbcAMP, known inducers of endoderm formation [14].
• Mouse heterozygotes for a null Gata4 allele have enhanced susceptibility to doxorubicin cardiotoxicity [15].
• Zinc finger-containing transcription factor GATA-4 and homeodomain Nkx-2.5 govern crucial developmental fates and have been found to promote cardiogenesis in embryonic cells exposed to the differentiating agent DMSO [16].
• Transfection of CHF1/Hey2 into neonatal cardiomyocytes suppresses activation of an ANF reporter plasmid by the transcription factor GATA4, which has previously been shown to activate a hypertrophic transcriptional program [17].
• Treatment with nifedipine altered the mRNA expression of the transcription factor Gata4, which was absent in the developing ventricles, and the sarcomeric protein Mylpc (myosin light chain 2V), which was decreased distal to the left ventricle and was absent at the site of the developing right ventricle [18].

Physical interactions of Gata4

• This conserved enhancer contains two consensus GATA binding sites that are efficiently bound by the zinc finger transcription factor GATA4 and are completely required for enhancer function in vivo [19].

Regulatory relationships of Gata4

• Zfpm2 (also known as Fog-2) is a multi-zinc-finger protein that is co-expressed with Gata4 in the developing heart beginning at E8.5 (refs 8-10) [6].
• Treatment of Gata4 -/- embryoid bodies with retinoic acid induces expression of another GATA-binding protein, GATA-6, in both visceral and parietal endoderm cells [14].
• Sox7 plays crucial roles in parietal endoderm differentiation in F9 embryonal carcinoma cells through regulating Gata-4 and Gata-6 expression [20].
• Transcription factor GATA-4 is expressed in a sexually dimorphic pattern during mouse gonadal development and is a potent activator of the Müllerian inhibiting substance promoter [21].
• We speculate that transcription factor GATA-4 may also control other genes involved in extracellular matrix formation in the yolk sac [22].

Other interactions of Gata4

• We demonstrate that Gata4 and Gata6 have overlapping expression patterns in the early pancreatic epithelium [23].
• Conversely, the majority of transgenic Gata4-Engrailed embryos do not have a pancreatic phenotype [23].
• In addition, we show Gata6, but not Gata4, physically interacts with Nkx2.2, an essential islet transcription factor [23].
• Furthermore, the activity of the Gata4 lateral mesoderm enhancer is attenuated by the BMP antagonist Noggin, and the enhancer is not activated in Bmp4-null embryos [11].
• This loop arose in consequence of it that p204 overcame the inhibition of the synergistic activity of Gata4 and Nkx2.5 by the Id proteins [24].

Analytical, diagnostic and therapeutic context of Gata4

• Mechanistically, cardiac-specific deletion of Gata4 increased cardiomyocyte TUNEL at baseline in embryos and adults as they aged, as well as dramatically increased TUNEL following pressure overload stimulation [2].
• We correlate their expression with that of muscle markers and the transcription factor GATA-4, using the reverse transcription-polymerase chain reaction (RT-PCR) [25].

References