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First published online 16 August 2006
doi: 10.1242/dev.02519

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Development of heart valves requires Gata4 expression in endothelial-derived cells

José Rivera-Feliciano¹, Kyu-Ho Lee^2,*, Sek Won Kong², Satish Rajagopal², Qing Ma², Zhangli Springer², Seigo Izumo³, Clifford J. Tabin¹ and William T. Pu^2,

¹ Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
² Department of Cardiology, Children's Hospital and Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA.
³ Cardiovascular Division, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215, USA.

Author for correspondence (e-mail: wpu{at}enders.tch.harvard.edu)

Accepted 5 July 2006

Cardiac malformations due to aberrant development of the atrioventricular (AV) valves are among the most common forms of congenital heart disease. At localized swellings of extracellular matrix known as the endocardial cushions, the endothelial lining of the heart undergoes an epithelial to mesenchymal transition (EMT) to form the mesenchymal progenitors of the AV valves. Further growth and differentiation of these mesenchymal precursors results in the formation of portions of the atrial and ventricular septae, and the generation of thin, pliable valves. Gata4, which encodes a zinc finger transcription factor, is expressed in the endothelium and mesenchyme of the AV valves. Using a Tie2-Cre transgene, we selectively inactivated Gata4 within endothelial-derived cells. Mutant endothelium failed to undergo EMT, resulting in hypocellular cushions. Mutant cushions had decreased levels of Erbb3, an EGF-family receptor essential for EMT in the atrioventricular cushions. In Gata4 mutant embryos, Erbb3 downregulation was associated with impaired activation of Erk, which is also required for EMT. Expression of a Gata4 mutant protein defective in interaction with Friend of Gata (FOG) cofactors rescued the EMT defect, but resulted in a decreased proliferation of mesenchyme and hypoplastic cushions that failed to septate the ventricular inlet. We demonstrate two novel functions of Gata4 in development of the AV valves. First, Gata4 functions as an upstream regulator of an Erbb3-Erk pathway necessary for EMT, and second, Gata4 acts to promote cushion mesenchyme growth and remodeling.

Key words: Heart development, Endocardial cushion, Gata4, Heart valves, Cardiac development, Cardiac morphogenesis, Epithelial-mesenchymal transition, EMT, Atrioventricular valves

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