Abstract 13462: Gata-5 is Required in Endocardial Cells for Proper Formation of the Aortic Valve
A key step in aortic valve development is the formation of the endocardial cushions (ECs) in the outflow tract (OFT). Subtle changes during this process can lead to congenital heart defects (CHDs) such as bicuspid aortic valve (BAV). BAV is the most common CHD in humans with an estimated rate of 1-2% in the population. However, very few genes have been linked to this defect and the mechanisms underlying BAV formation remain undefined. In humans, mutations in the Notch1 gene have been associated with BAV, whereas in mice, inactivation of NOS3 leads to a 40% penetrance of BAV formation. GATA-5, a member of the GATA family of transcription factors, is expressed in a spatial and temporal manner in the developing heart where it is predominantly found in endocardial cells and ECs of the OFT and atrioventricular canal between E9.5-E12.5 in the mouse. Mutations in the Gata-5 gene in zebrafish (faust mutants) cause cardia bifida and lead to endocardial cell depletion. In vitro studies using antisense mRNA against Gata-5 revealed a critical role for this gene in differentiation of endocardial cells. We generated a Gata-5 knockout allele by deleting the exons encoding the second zinc finger, which is critical for DNA binding, as well as the whole C-terminus. Over 26% of Gata-5 null mice developed BAVs. Moreover, endocardial specific deletion of Gata5 obtained by crossing mice with floxed (Flox) Gata5 alleles with Tie2-cre transgenic mice resulted in a similar penetrance of BAVs, as in Gata5-/- mice. RNA profiling revealed that Jag-1, a co-receptor for Notch1, is significantly downregulated in both Gata-5 null and Tie2-cre+;Gata5Flox/Flox mice, suggesting that disruption of Notch signaling in endocardial cells may be the underlying mechanism of disease. These findings establish that expression of GATA-5 in endocardial cells is critical for aortic valve formation and identify Jag-1 as a candidate congenital heart disease causing gene in human.
- © 2010 by American Heart Association, Inc.