During early stages of heart development, the linear heart tube (LHT) expands to create cardiac chambers with characteristic curvatures: a convex outer curvature (OC) and a concave inner curvature (IC). This stereotypical chamber shape facilitates the effective function of the embryonic heart, and errors in chamber morphogenesis are frequently associated with congenital heart disease. During my postdoctoral studies, I aspire to elucidate essential cellular and molecular mechanisms that regulate chamber curvature morphogenesis, using zebrafish as a model organism. At the cellular level, we have previously shown that regional changes in cardiomyocyte (CM) morphologies underlie curvature formation: as the ventricle emerges, the apical surface of OC cells becomes large and elongated, whereas the apical surface of IC cells remains relatively small and circular, similar to cells of the primitive LHT. However, the subcellular mechanisms that regulate these cell behaviors remain elusive. My preliminary studies add a new dimension to our model for curvature formation: whereas OC cells remain relatively flat, similar to cells of the LHT, IC cells extend along their apicobasal (AB) axis. Coupled with this difference in AB length, I find distinct F-actin organization in each curvature: whereas F-actin is enriched in the basal domain of OC cells, it expands apically in IC cells, suggesting a link between actin dynamics and patterns of cell shape change. Consistent with this, I have found that inhibition of actin polymerization disrupts curvature-specific CM shapes. Synthesizing my data with prior studies, I hypothesize that ventricular curvature formation involves 1) IC cell acquisition of cuboidal morphology 2) OC cell acquisition of squamous morphology, and 3) patterned reorganization of F-actin in these regions. Here, I propose to test each tenet of this model. First, I will establish the connection between F-actin organization and curvature-specific cell shape changes by examining regional actin dynamics and individual cell dimensions throughout chamber emergence. In addition, I will test whether the acquisition of curvature- specific traits is dependent on the function of Tbx5, an established regulator of chamber emergence. Second, I will extend my preliminary studies to determine what types of actin dynamics (polymerization, depolymerization, and branching) are required for the attainment of OC and IC cell morphologies. Additionally, I will test whether actin dynamics act cell autonomously to influence CM shapes in the OC and IC. Finally, I will identify potential regulators of patterned F-actin organization using a single-cell RNA-sequencing approach to compare expression profiles of OC and IC cells. Intriguingly, our initial datasets already highlight actin regulators and other cell biologically relevant genes that are differentially expressed in putative OC and IC cells. Altogether, this work is likely to provide a new model for how localized regulation of actin dynamics creates patterns of CM morphologies that underlie chamber curvature formation, and it may also shed light on mechanisms through which chamber development could go awry in the context of congenital heart disease.

Public Health Relevance

Congenital heart defects are present in about 1% of U.S. newborns, and these defects frequently include alterations in cardiac chamber morphology. Although the specific shape of the developing heart has been well characterized, the molecular and cellular mechanisms that create this shape remain mysterious. A better understanding of these mechanisms will help us to identify the etiology of these prevalent birth defects.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Postdoctoral Individual National Research Service Award (F32)
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Special Emphasis Panel (ZRG1)
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Meadows, Tawanna
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University of California, San Diego
Schools of Arts and Sciences
La Jolla
United States
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