Gata4 and Gata5 Cooperatively Regulate Cardiac Myocyte Proliferation in Mice

Department of Cell and Developmental Biology, University of Pennsylvania, Philadelphia, PA 19104, USA.
Journal of Biological Chemistry (Impact Factor: 4.57). 11/2009; 285(3):1765-72. DOI: 10.1074/jbc.M109.038539
Source: PubMed


GATA5 is a member of the zinc finger transcription factor GATA family (GATA1-6) that plays a wide variety of roles in embryonic and adult development. Experiments in multiple model systems have emphasized the importance of the GATA family members 4-6 in the development of the endoderm and mesoderm. Yet despite overlapping expression patterns, there is little evidence of an important role for GATA5 in mammalian cardiac development. We have generated a new Gata5 mutant allele lacking exons 2 and 3 that encodes both zinc finger domains (Gata5(tm)(2)(Eem)), and we show that although Gata5(-/-) mice are viable, Gata4(+/-)5(-/-) mutants die at mid-gestation and exhibit profound cardiovascular defects, including abnormalities of cardiomyocyte proliferation and cardiac chamber maturation. These results demonstrate functional redundancy between Gata4 and Gata5 during cardiac development and implicate Gata5 as a candidate modifier gene for congenital heart disease.

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    • "AMERICAN JOURNAL OF MEDICAL GENETICS PART A involved in the activation of several developmental genes and is important in maintaining primordial germ cells in the mouse model [Weber et al., 2010]. An abnormal gene dosage of the GATA5 gene could be contributing to the cardiac malformations [Singh et al., 2009]. The MMP9 gene is involved in embryologic development , tissue remodeling, and has also been found to be involved in a neutrophil-induced pathway for angiogenesis [Ardi et al., 2007], which is interesting given our patient's persistent leukocytosis. "
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    ABSTRACT: Duplications of the terminal long arm of chromosome 20 are rare chromosomal anomalies. We report a male infant found on array comparative genomic hybridization analysis to have a 19.5 Mb duplication of chromosome 20q13.12-13.33, as well as an 886 kb deletion of 20p13 at 18,580-904,299 bp. This anomaly occurred as the recombinant product of a paternal pericentric inversion. There have been 23 reported clinical cases involving 20qter duplications; however, to our knowledge this is only the second reported patient with a paternal pericentric inversion resulting in 46,XY,rec(20)dup(20q). This patient shares many characteristics with previously described patients with 20qter duplications, including microphthalmia, anteverted nares, long ears, cleft palate, small chin, dimpled chin, cardiac malformations, and normal intrauterine growth. While there is variable morbidity in patients with terminal duplications of 20q, a review of previously reported patients and comparison to our patient's findings shows significant phenotypic similarity. © 2014 Wiley Periodicals, Inc.
    Full-text · Article · Aug 2014 · American Journal of Medical Genetics Part A
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    • "It is well documented that ROS regulates gene expression, cell proliferation and apoptosis [43]. In the present study, transcription factors that are critical to embryonic heart development including Gata4, Gata5[44,45] were downregulated in diabetic fetal hearts at E11.5. However similar to previous studies, Vegf-a mRNA levels were increased in diabetic fetal hearts [35]. "
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    ABSTRACT: Pregestational diabetes is a major risk factor of congenital heart defects (CHDs). Glutathione is depleted and reactive oxygen species (ROS) production is elevated in diabetes. In the present study, we aimed to examine whether treatment with N-acetylcysteine (NAC), which increases glutathione synthesis and inhibits ROS production, prevents CHDs induced by pregestational diabetes. Female mice were treated with streptozotocin (STZ) to induce pregestational diabetes prior to breeding with normal males to produce offspring. Some diabetic mice were treated with N-acetylcysteine (NAC) in drinking water from E0.5 to the end of gestation or harvesting of the embryos. CHDs were identified by histology. ROS levels, cell proliferation and gene expression in the fetal heart were analyzed. Our data show that pregestational diabetes resulted in CHDs in 58% of the offspring, including ventricular septal defect (VSD), atrial septal defect (ASD), atrioventricular septal defects (AVSD), transposition of great arteries (TGA), double outlet right ventricle (DORV) and tetralogy of Fallot (TOF). Treatment with NAC in drinking water in pregestational diabetic mice completely eliminated the incidence of AVSD, TGA, TOF and significantly diminished the incidence of ASD and VSD. Furthermore, pregestational diabetes increased ROS, impaired cell proliferation, and altered Gata4, Gata5 and Vegf-a expression in the fetal heart of diabetic offspring, which were all prevented by NAC treatment. Treatment with NAC increases GSH levels, decreases ROS levels in the fetal heart and prevents the development of CHDs in the offspring of pregestational diabetes. Our study suggests that NAC may have therapeutic potential in the prevention of CHDs induced by pregestational diabetes.
    Full-text · Article · Feb 2014 · Cardiovascular Diabetology
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    • "Based on our findings, 3 out of 4 patients with rare nonsynonymous GATA5 variants (Gln3Arg, Ser19Trp and Gly166Ser) have a rather modest clinical pathology, and it is possible that the homologous transcription factor GATA4 may partially compensate for reduced GATA5 activity [29]. All rare non-synonymous variants were identified in male patients, and while our BAV cohort comprises 77% males and BAV is more common in males, this may reflect a reduced expressivity of GATA5 mutations in females. "
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    ABSTRACT: Bicuspid aortic valve (BAV) is the commonest congenital heart disease and a highly heritable trait; however, only the NOTCH1 gene has been linked to limited cases of BAV in humans. Recently, the transcription factor GATA5 has been shown to have an essential role in aortic valve development, and targeted deletion of Gata5 in mice is associated with partially penetrant BAV formation. Here, we investigated the relationship between GATA5 gene variants and BAV with its associated aortopathy. One hundred unrelated individuals with confirmed BAV were prospectively recruited. Following collection of clinical information and DNA extraction, the coding regions and splice signal sequences of the GATA5 gene were screened for sequence variations. The clinical characteristics of the cohort included a male predominance (77%), mean age of diagnosis 29 ± 22 years, associated aortopathy in 59% and positive family history for BAV in 13%. Genetic analysis identified the presence of 4 rare non-synonymous variations within the GATA5 transcriptional activation domains, namely Gln3Arg, Ser19Trp, Tyr142His and Gly166Ser, occurring in one patient each. Gln3Arg and Tyr142His substitutions affect highly conserved and functionally relevant residues, and are likely to impact on the transcriptional activation of GATA5 target regions. A novel Ser19Trp variation was identified at a highly conserved amino acid residue in one patient, while the Gly166Ser variant was found in a familial case of BAV and associated aortopathy. Rare non-synonymous variations in the functionally important GATA5 transcriptional activation domains may be important in the pathogenesis of BAV disease in humans.
    Full-text · Article · May 2012 · Journal of Molecular and Cellular Cardiology
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