The role of Tbx2 in cardiac development and cell cycle regulation

The T-box genes form an evolutionarily ancient family that encodes transcription factors which are definitively related by the presence of a DNA binding motif called the T-box. Members of this gene family have been shown to perform crucial developmental functions. Several T-box genes exhibit specific expression profiles in the developing heart, including Tbx2 and Tbx3 , and some have been shown to perform essential functions during cardiogenesis. The thesis work presented here has utilized a targeted Tbx2 deletion allele to investigate the potential developmental roles of the gene, with particular emphasis on cardiogenesis and cell cycle regulation.; A detailed cardiac expression analysis revealed that Tbx2 is expressed as early as in cardiac crescent mesoderm at 8.5 days post coitus (dpc). During midline heart tube formation, Tbx2 is expressed in the inflow tract and is specifically excluded from the ventricle. Tbx2 expression becomes apparent in outflow tract (OFT) myocardium during heart tube looping. By 9.5 dpc, cardiac expression of Tbx2 is present in a continuous anterior-posterior zone that spans between the OFT and inflow tract via the inner curvature, and which also includes the atrioventricular canal (AVC).; Mice heterozygous for a targeted deletion in the Tbx2 locus are viable, fertile, and grossly normal. Homozygous mutants die between 10.5 and 14.5 dpc. A fraction of homozygous mutants display abnormal atrioventricular morphology at 9.5 dpc. A similar subset of homozygous mutants display symptoms of cardiac insufficiency at 10.5 dpc. Approximately half of homozygous mutant embryos are dead by 11.5 dpc. Molecular analysis showed that all homozygous mutants display ectopic atrioventricular expression of chamber-specific genes, despite indications that the AVC is normally specified. Notably, ectopic chamber differentiation was not observed in the OFT.; Of the homozygous mutants that survive beyond 11.5 dpc, approximately half display signs of cardiac insufficiency by 12.5 dpc. Morphological and histological analyses of homozygous mutants at this stage revealed OFT remodeling defects of varying severity. In many cases, the OFT is incompletely septated by 12.5 dpc, and is frequently accompanied by abnormal positioning of the presumptive aorta relative to the inter-ventricular septum and left ventricle. Molecular analysis revealed that the secondary heart field is apparently uncompromised and capable of making a normal contribution to anterior heart structures at 12.5 dpc. (Abstract shortened by UMI.)...