Congenital heart defects account for the largest number of birth defects in humans. Many heart defects can be attributed to abnormalities in specific steps in cardiac development, particularly in the formation and function of the ventricular chambers and in the neural crest-derived components of the heart. While the embryologic events involved in heart development have been carefully documented, little is known of the underlying mechanisms and molecules that control cardiac myogenesis and morphogenesis. The overall goal of this project is to elucidate the molecular mechanisms involved in specification and development of the ventricular chambers and the cardiac neural crest and to identify the genes responsible for defects in these cardiac compartments in three human chambers and the cardiac neural crest and to identify the genes responsible for defects in these cardiac compartments in three human syndromes associated with congenital heart disease: hypoplastic left heart syndrome, Down syndrome, and DiGeorge syndrome. Recently, the Olson lab found that two novel bHLH transcription factors, referred to as dHAND and eHAND, are expressed in specific subsets of ventricular precursor cells and in the cardiac neural crest and that mouse mutants lacking dHAND fail to form a right ventricle specification and cardiac neural crest and that mouse mutants lacking dHAND fail to form a right ventricle or cardiac neural crest derivatives. The discovery of these molecules provides a molecular entry point into the mechanisms for ventricular specification and cardiac neural crest development and establishes a conceptual framework for the overall SCOR. The SCOR contains four interwoven projects and three cores that encompass basic molecular strategies to understand cardiac development and clinical studies to identify the gens responsible for congenital heart diseases in which the ventricular and neural crest components of the heart are affected. The projects are as follows. 1) E. Olson will define the roles of the HAND family of cardiac basic helix-loop-helix (bHLH) transcription factors in normal and abnormal cardiac development. 2) D. Srivastava will define the downstream target genes regulated by dHAND in the developing heart, with particular attention to a recently discovered gene that is dHAND-dependent and is localized to the minimal chromosomal deletion in DiGeorge syndrome. 3) K. Chien will clone and characterize the gene responsible for hypoplastic left heart syndrome. 4) Korenberg will identify the gene(s) responsible for heart defects in Down syndrome. The possibility that one of the candidate genes, which encodes a novel cell adhesion molecule, called DS-CAM, is a transcriptional target for MEF2 will also be addressed. Each of these projects is interrelated through the creation of novel strains of mouse mutants in which key cardiogenic regulatory genes can be inactivated in a temporal- and compartment-specific manner within the developing heart. These studies will provide an in-depth understanding of the basic molecular pathways that regulate heart development and the ways in which these pathways can be disrupted in congenital heart diseases.
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