Disruption of myocardial Gata4 and Tbx5 results in defects in cardiomyocyte proliferation and atrioventricular septation
| Autor: | Nianyuan Huang, Sheng-Wei Chang, Madhumita Basu, Vidu Garg, Chaitali Misra |
|---|---|
| Rok vydání: | 2014 |
| Předmět: |
Heterozygote
endocrine system Organogenesis Gene Expression Mice Morphogenesis Genetics medicine Animals Myocyte Cell Lineage Myocytes Cardiac Molecular Biology reproductive and urinary physiology Genetics (clinical) Endocardium Mice Knockout biology Heart development GATA4 Heart Septal Defects Myocardium Cyclin-Dependent Kinase 2 Cardiac myocyte Cyclin-dependent kinase 2 Cyclin-Dependent Kinase 4 Gene Expression Regulation Developmental Epistasis Genetic Heart Articles General Medicine Anatomy respiratory system Embryo Mammalian GATA4 Transcription Factor Cell biology Disease Models Animal medicine.anatomical_structure Ventricle embryonic structures cardiovascular system biology.protein T-Box Domain Proteins Chromatin immunoprecipitation |
| Zdroj: | Human Molecular Genetics. 23:5025-5035 |
| ISSN: | 1460-2083 0964-6906 |
| DOI: | 10.1093/hmg/ddu215 |
| Popis: | Mutations in GATA4 and TBX5 are associated with congenital heart defects in humans. Interaction between GATA4 and TBX5 is important for normal cardiac septation, but the underlying molecular mechanisms are not well understood. Here, we show that Gata4 and Tbx5 are co-expressed in the embryonic atria and ventricle, but after E15.5, ventricular expression of Tbx5 decreases. Co-localization and co-immunoprecipitation studies demonstrate an interaction of Gata4 and Tbx5 in the developing atria and ventricles, but the ventricular interaction declines after E14.5. Gata4(+/-);Tbx5(+/-) mouse embryos display decreased atrial and ventricular myocardial thickness at E11.5, prior to cardiac septation. To determine the cell lineage in which the interaction was functionally significant in vivo, mice heterozygous for Gata4 in the myocardium or endocardium and heterozygous for Tbx5 (Gata4(MyoDel/wt);Tbx5(+/-) and Gata4(EndoDel/wt);Tbx5(+/-), respectively) were generated. Gata4(MyoDel/wt);Tbx5(+/-) mice displayed embryonic lethality, thin myocardium with reduced cell proliferation, and atrioventricular septation defects similar to Gata4;Tbx5 compound heterozygotes while Gata4(EndoDel/wt);Tbx5(+/-) embryos were normal. Cdk4 and Cdk2, cyclin-dependent kinases required for myocardial development and septation were reduced in Gata4(+/-);Tbx5(+/-) hearts. Cdk4 is a known direct target of Gata4 and the regulation of Cdk2 in the developing heart has not been studied. Chromatin immunoprecipitation and transactivation studies demonstrate that Gata4 and Tbx5 directly regulate Cdk4 while only Tbx5 activates Cdk2 expression. These findings highlight the mechanisms by which disruption of the Gata4 and Tbx5 interaction in the myocardium contributes to cardiac septation defects in humans. |
| Databáze: | OpenAIRE |
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