Abstract 15469: Med10 Regulates the Formation of the Atrioventricular Canal by Controlling Tbx2b Expression in the Embryonic Zebrafish Heart
The genetic and molecular mechanisms that guide valvulogenesis are mostly unknown but of immense importance for biomedical research since heart valve diseases account for up to 30% of all congenital cardiovascular malformations. The zebrafish cardiac valve mutant ping pong (png) displays a pathologically developed atrioventricular canal accompanied by absent endocardial cushions, the precursors of the cardiac valves and vigorous regurgitation of blood between the atrial and ventricular chamber. By positional cloning, we identified an insertional promoter mutation within the zebrafish mediator complex subunit 10 (med10) gene leading to severely diminished med10 transcription and thereby to deficient endocardial cushion development. Injection of med10 mRNA in png mutant embryos restores the wild-type phenotype in these embryos. Interestingly, we find complete loss of tbx2b expression in the AV canal of png mutant hearts and demonstrate that transient reconstitution of Tbx2b expression rescues AV canal development in png mutant zebrafish. By contrast, overexpression of Foxn4, a known upstream regulator of Tbx2b, is not capable to reconstitute Tbx2b expression and thereby the formation of endocardial cushions in Med10-deficient png mutant hearts, suggesting a crucial role of Med10 in mediating Foxn4 signals and activating tbx2b transcription. Thus, we provide for the first time evidence that heart valve development depends on the proper function of Med10 by regulating Foxn4-Tbx2b signaling in the developing AV canal.
- © 2012 by American Heart Association, Inc.