Development of heart valves requiresGata4expression in endothelial-derived cells

Abstract

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 endothelialderived 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.

Noonan syndrome cardiac defects are caused by PTPN11 acting in endocardium to enhance endocardial-mesenchymal transformation

“…AV explant cultures and immunostaining were performed as described (32). Where indicated, U0126, AG825, AG1478, PD173074 (Calbiochem) or Tarceva were added after 24 h of culture.…”

Combinatorial regulation of tissue specification by GATA and FOG factors

“…Conditional ablation of GATA4 in endothelial cells also resulted in hypocellular endocardial cushions (Rivera-Feliciano et al, 2006). In this case, the defect can likely be attributed to failure of the endothelial cells to undergo epithelial-to-mesenchymal transition (EMT), which is required for derivation of the mesenchymal cells of the cushions.…”

Tbx20 acts upstream of Wnt signaling to regulate endocardial cushion formation and valve remodeling during mouse cardiogenesis

“…S6). The expression of other genes crucial for endocardial cushion and valve development, including Bmp4 (Jiao et al, 2003), Notch1 (Timmerman et al, 2004), Gata4 (Rivera-Feliciano et al, 2006), Tbx5 (Nadeau et al, 2010) and Nfatc1 (de la Pompa et al, 1998;Ranger et al, 1998) was unchanged in Tbx20 CKO hearts (supplementary material Figs S7, S8). These results suggest that endocardial Tbx20 is not essential for EMT initiation in the AVC or OFT.…”