Cellular Mechanisms of Cardiac Trabeculae Formation

University Of California, San Diego, La Jolla CA

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Abstract

DESCRIPTION (provided by applicant): The overall objective of this proposed study is to examine the cellular mechanisms underlying directional cardiomyocyte migration during trabeculation. Structural malformation is a major contributing factor towards congenital heart diseases. Conditions that affect ventricular trabeculation, either by hypotrabeculation or hypertrabeculation (such as left ventricular noncompaction) result in poor cardiac function and poor clinical outcome. Cardiac trabeculae are cardiomyocyte (CM) ridges that protrude into the lumen of the heart lined with endocardial cells. They contribute to the cardiac conduction system and papillary muscles; thus they are indispensable for cardiac function. Directional cell migration is a major contributing factor to cardiac trabeculae morphogenesis. Although previous studies have identified signaling pathways that facilitate trabeculae formation, the underlying cellular mechanism by which the CMs migrate towards the ventricular lumen to form trabeculae remains elusive. We have recently generated genetic tools to examine the role of planar cell polarity pathway (PCP), a known pathway that facilitates directional cell migration, during cardiac trabeculation in the zebrafish. Our guiding hypothesis is that CMs migrate towards the ventricular lumen by directionally extending their lamellipodia. Furthermore, the neuregulin-ErbB2 and the PCP pathways work synergistically to regulate the formation and directional orientation of lamellipodia in migrating CMs to promote trabeculae formation. To test our hypothesis, we propose: 1) To examine whether migrating cardiomyocytes form lamellipodia and whether lamellipodia have directional alignment in vivo, 2) To examine the molecular mechanisms that mediate directional migration of cardiomyocytes during trabeculae formation, 3) To examine whether neuregulin-ErbB2 signaling may be an upstream regulator of directional migration by promoting lamellipodia formation. High resolution, in vivo imaging of the developing zebrafish heart will be carried out to capture the cellular events facilitating trabeculation. Clonl analysis of CMs with defective PCP signaling will be carried out to examine the role of the PCP pathway in regulating CM directional migration by orienting their lamellipodia. Furthermore, the potential role of neuregulin- ErbB2 pathway as an upstream regulator of the PCP pathway will be examined by loss of function studies using pharmacological inhibitors. Understanding the cellular mechanisms underlying cardiac trabeculation will have profound impact on identifying the etiology and potential therapeutic targets for congenital heart diseases caused by malformation of cardiac trabeculation.