Over the course of development, the heart transforms from an epithelial layer of myocytes to a complex, three-dimensional structure critical for its function. A number of morphogenetic processes contribute to this transformation, and one of these processes leads to the formation of the cardiac trabeculae, sheet-like muscular structures in the ventricular myocardial wall. Trabeculae play a critical role in increasing myocardial mass before the development of a coronary circulatory system, and serve as precursors for the ventricular conduction system. Additionally, failure to form trabeculae or failure of ventricular compaction can cause congenital cardiomyopathies. Despite the importance of these structures, there remain many open questions about how they are formed. In this proposal, we will use the powerful live imaging and transgenic approaches available with the zebrafish system to examine the cellular and molecular determinants of trabecular formation. How individual myocytes enter the trabecular layer is currently unknown. Our initial data suggest that trabeculae form via a process of delamination, but the precise cellular mechanisms remain unclear. We hypothesize that myocytes use the conserved developmental process of apical constriction to exit the compact layer and form trabecular sheets. To test this hypothesis, we will use mosaic expression of fluorescent proteins combined with live imaging to monitor the cell shape changes of individual cardiomyocytes within the zebrafish ventricle. Additionally, we will use a combination of live imaging and immunofluorescence to examine the behavior of actin and myosin during this process. Only some cells within the ventricular myocardium contribute to the trabecular layer, and how these cells are chosen is currently unknown. The Notch pathway plays many roles in development, and is known to regulate asymmetric cell fate decisions in a variety of contexts. Our initial data suggest that Notch signaling within myocytes is restricted to the compact layer. We hypothesize that activation of Notch signaling prevents cells from contributing to trabeculae. We propose to test this hypothesis by monitoring Notch activation over time using a transgenic zebrafish line expressing GFP under a notch-responsive promoter. Further, we will use mosaic expression of dominant activators and repressors of the Notch pathway to determine whether Notch activation is necessary and sufficient for preventing trabecular incorporation. By using the powerful imaging and genetic tools available in the zebrafish system, this proposal will shed light on the mechanisms controlling trabecular formation at a cellular level.

Public Health Relevance

Cardiac trabeculae are sheet-like muscular structures within the ventricles of the heart that play a role in both contraction and electrical conduction within te ventricular chambers. Despite their functional importance, little is known about how cells physically enter the trabeculae, or what signals tell some, but not all, myocardial cells to form these trabeculae. This proposal seeks to understand how cells make the decision to enter the trabeculae, and, once they do, how they move and change shape to form these structures.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Individual Predoctoral NRSA for M.D./Ph.D. Fellowships (ADAMHA) (F30)
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Special Emphasis Panel (ZRG1-F05-P (20))
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Meadows, Tawanna
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University of California San Francisco
Schools of Medicine
San Francisco
United States
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Staudt, David W; Liu, Jiandong; Thorn, Kurt S et al. (2014) High-resolution imaging of cardiomyocyte behavior reveals two distinct steps in ventricular trabeculation. Development 141:585-93