Transcriptional Regulation During Cardiovascular Development




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Heart development is a complex and tightly regulated process involving cell-fate specification, differentiation, and organogenesis. A network of transcription factors play pivotal roles in regulating each step during cardiogenesis. The zinc-finger proteins GATA4 and GATA6 are two closely related transcription factors expressed early during heart development. Although mice that are heterozygous for either a GATA4 or GATA6 null allele are normal, compound heterozygosity of GATA4 and GATA6 results in embryonic lethality by E13.5 accompanied by a spectrum of cardiovascular defects, abnormal smooth muscle development with reduced proliferation of cardiomyocytes and down regulation of MEF2C and the embryonic contractile protein beta -MHC. These results exemplify the strict regulation of heart development by revealing that the dose threshold of these two transcription factors is essential for proper cardiovascular development. The basic helix-loop-helix transcriptional repressor Hairy-related transcription factor-2 (Hrt2), a direct target of Notch signaling, is expressed in ventricular but not atrial cardiomyocytes, as well as in endothelial and vascular smooth muscle cells. To elucidate the cell autonomous function of Hrt2 in cardiac cell lineages, I generated a conditional Hrt2 null allele using the loxP-Cre system. Cardiomyocyte-specific deletion of Hrt2 in mice results in ectopic activation of atrial genes in ventricular myocardium with an associated impairment of cardiac contractility and a unique distortion in morphology of the right ventricular chamber. Furthermore, forced expression of Hrt2 in atrial cardiomyocytes is sufficient to repress atrial cardiac genes. These results suggest that, consistent with its expression pattern, Hrt2 functions as a repressor in the ventricular cardiomyocyte to suppress atrial cell identity and the maintenance of post-natal cardiac function. These studies reveal important functions of the transcription factors GATA4, GATA6 and Hrt2 in cardiovascular development.

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