Requirements for hedgehog signaling during vertebrate heart development and septation

The mammalian heart must undergo a series of additions and septation events in its transformation from a single-chamber, linear tube into a four-chambered structure. Disruption of these events leads to congenital heart defects, the most common type of human birth defect. Expression patterns of Hedgehog (Hh) signaling components and mouse knockout phenotypes of Sonic hedgehog and Smoothened implicate Hh signaling as a potential mediator of multiple aspects of early cardiac development and septation. In particular, loss of the Hh ligand, Sonic hedgehog, results in outflow tract (OFT) mal-development and subsequent septation defects, as well as abnormal atrioventricular septation. To assess the roles of Hh signaling in heart development and septation we performed a series of tissue specific genetic manipulations within the mouse.; Two critical fields involved in the development of the OFT are the cardiac neural crest cells (CNCCs) and the anterior heart field (AHF), which are required in part for OFT septation and myocardial cell generation of the right ventricle/OFT, respectively. The CNCCs and AHF are both affected in Hh pathway knockout mice. Through our studies we have found three roles for Hh signaling in the OFT: Hh is a direct survival factor for the CNCC, an indirect AHF survival factor and a direct septation signal required by the AHF. These results implicate endodermal Sonic hedgehog signaling as a mediator of CNCC and AHF contribution to the OFT.; Endodermal Hh signaling is also required for atrioventricular septation. Sonic hedgehog mouse mutants have a constellation of intracardiac septation defects termed "atrioventricular septation defect". Classical analysis of this defect focused on the development of the atrioventricular cushions; however, we found that these structures do not require direct Hh signaling for normal development. Through analysis of a series of conditional ablation mouse mutants we uncovered a direct requirement for Hh signaling to the dorsal mesocardium. These extra-cardiac cells protrude into the atria and form the atrial spine, a largely unrecognized component of the atrioventricular septation complex. Loss of Hh signaling results in the failure to form the atrial spine and abnormal development of the rest of the atrioventricular complex.