Molecular regulation of ventricular chamber maturation

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Abstract Congenital heart diseases are the most common type of human birth defects, and many of these diseases feature structural abnormalities that emerge during development. In order to meet an increasing physiological demand of the growing embryo, the developing heart undergoes complex morphogenetic changes to optimize its ventricular myoarchitecture for more efficient contraction. This proposal is focused on ventricular maturation that is characterized by the formation of muscular protrusions called cardiac trabeculae. Our prior studies revealed that cardiac trabeculation is initiated by directional cardiomyocyte migration from the compact layer, and that ErbB2 cell-autonomously regulates this process. We also found that biomechanical forces generated by the functioning embryonic heart is required for cardiac trabeculation. However, several outstanding questions remain to be addressed, including those related to 1) the mechanism by which mechanical stimulus is sensed and translated into spatial and temporal signals to regulate cardiac trabeculation and 2) the exact function of cardiac trabeculae in the heart. It has been recognized that there exists an intimate relationship between cardiac function and cardiac form. In this research program, we hypothesize that mechanical-biochemical interaction is essential for cardiac trabecular formation and induces pathological hypertrophic remodeling in the absence of trabecular formation. In support of this hypothesis, we found that primary cilia-mediated flow sensing is required for trabeculation through activation of Notch signaling in the ventricular endocardium. While biomechanical forces are required to initiate trabeculation, our preliminary study also revealed an essential role of cardiac trabeculae in handling the mechanical forces generated by cardiac contraction. To test our hypothesis, we propose to further delineate the mechanical-biochemical cellular signaling responsible for 1) trabecular formation, and 2) cardiac dysfunction due to trabecular malformation. The successful completion of this proposal will not only define the molecular and cellular mechanisms of ventricular maturation but also provide further mechanistic insight into the inter-relationship between cardiac function and cardiac form.