Abstract
The T-box transcription factor TBX1 has critical roles in maintaining proliferation and inhibiting differentiation of cardiac progenitor cells of the second heart field (SHF). Haploinsufficiency of the gene that encodes it is a cause of congenital heart disease. Here, we developed an embryonic stem (ES) cell-based model in which Tbx1 expression can be modulated by tetracycline. Using this model, we found that TBX1 down regulates the expression of VEGFR2, and we confirmed this finding in vivo during embryonic development. In addition, we found a Vegfr2 domain of expression, not previously described, in the posterior SHF and this expression is extended by loss of Tbx1. VEGFR2 has been previously described as a marker of a subpopulation of cardiac progenitors. Clonal analysis of ES-derived VEGFR2+ cells indicated that 12.5% of clones expressed three markers of cardiac lineage (cardiomyocyte, smooth muscle and endothelium). However, a pulse of Tbx1 expression was sufficient to increase the percentage to 20.8%. In addition, the percentage of clones expressing markers of multiple cardiac lineages increased from 41.6% to 79.1% after Tbx1 pulse. These results suggest that TBX1 plays a role in maintaining a progenitor state in VEGFR2+ cells.
Highlights
The majority of the cardiac cells derives from two separate populations of progenitors named “heart fields” [1]
TBX1 plays a key role in the control of proliferation and differentiation of cardiac progenitor cells of the second heart field (SHF), and in tissue culture it marks cells with cardiomyocyte, smooth muscle and endothelial differentiation potential [9]
In this work we provide the first evidence that TBX1 suppresses the expression of the Vegfr2 gene in differentiating embryonic stem (ES) cells and during embryonic development
Summary
The majority of the cardiac cells derives from two separate populations of progenitors named “heart fields” [1]. TBX1 is a transcription factor expressed in several tissues but its early expression in mesodermal tissue is important for normal development of SHF-derived heart segments, especially the OFT [5,6,7]. Mesodermal-specific deletion of Tbx down regulates cell proliferation in the SHF [8] revealing its role in the expansion of cardiac progenitors [9]. Cre recombination-based cell tracing has shown that descendants of Tbx1-expressing cells populate myocardial and endocardial layers of the OFT and RV and, to a lesser extent the right atrium [5,10]
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