Mechanisms of DMP Development and Atrioventricular Septation

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DESCRIPTION (provided by applicant): Atrioventricular septal defects (AVSDs) are congenital heart malformations found in approximately 5% of all individuals suffering from congenital heart disease (CHD). They are particularly common in individuals with Down Syndrome (DS) and in patients with heterotaxy syndrome. While it was believed for many years that abnormal development of atrioventricular cushions was the only mechanism involved in the pathogenesis of these defects, more recent studies have revealed that perturbation of tissues derived from the posterior Second Heart Field (pSHF) located at the venous pole of the heart, including the primary atrial septum and the Dorsal Mesenchymal Protrusion (DMP), play a critical role in the pathogenesis of AVSDs as well. In this application we propose to investigate the synergistic relationship between three signaling pathways that are involved in the regulation of pSHF/DMP development and in the formation of the AV septal complex, i.e. the Hedgehog (Hh) signaling pathway, the Wnt(2)/�-catenin pathway, and the BMP signaling pathway. Some of the molecular mechanisms implicated in pathogenesis of AVSDs are also involved in the assembly and/or function of primary cilia, which, as we have established, are also present on pSHF cells. The fact that abnormalities in the function and/or structure of cilia are associated with the pathogenesis of AVSDs, in combination with a series of observations and preliminary results outlined in the proposal, has led to the overarching hypothesis that the Wnt/�-catenin and BMP signaling pathways in the pSHF are part of a complex molecular network orchestrating the development of the pSHF and are located down-stream of the cilia-associated Shh pathway.