Research

 

Cardiac Specification

The number of cardiac progenitor cells is a significant determinant of heart size (Keegan, Meyer, and Yelon, 2004). Several factors, including Bmp2, Fgf8, Nodal, and Wnt 11, have been implicated in promoting the assignment of cardiac identity (reviewed in Brand, 2003). However, much less is known about the opposing factors that set limits for cardiac progenitor specification. We have therefore also focused our attention on zebrafish mutants with large hearts composed of too many cardiomyocytes. Notably, our recent analyses of these mutants have revealed two potent mechanisms for restricting the formation of cardiac progenitors. These studies indicate that generation of the proper number of progenitors involves interplay between inductive and repressive pathways.

Chamber Progenitors

RA Signaling

Cardiac Morphogenesis

Following cardiac specification and differentiation, a complex choreography of cardiomyocyte cell behaviors generates the characteristic shapes of the cardiac chambers. Chamber shape can be sculpted by cell movement, cell division, or changes in cell size and shape, and all of these cellular activities can be influenced by the surrounding environment. Very little is known about the molecular and cellular mechanisms that regulate this elaborate process. By combining high-resolution live imaging with genetic analysis, we can elucidate pathways with a crucial influence on the actions of individual cardiomyocytes. To date, we have focused our attention on two particular steps of cardiac morphogenesis: the midline merger of the bilateral cardiomyocyte populations and the emergence of chamber curvatures. During both of these processes, regionally restricted patterns of cell behavior underlie key features of cardiac morphology.

Zebrafish

To study the mechanisms regulating heart size and shape, we take advantage of the unique arsenal of experimental approaches available in zebrafish. A large part of the appeal of the zebrafish derives from the transparency of its embryo, which permits high-resolution inspection of heart size, shape, and function. Additionally, the zebrafish has proven to be excellent for largescale genetic screens and subsequent identification of mutated genes. Screening for cardiac phenotypes is particularly effective, since the zebrafish embryo does not require a functional cardiovascular system for its survival during embryogenesis. By combining the benefits of zebrafish genetics and embryology, we can identify crucial regulators of chamber formation and determine their precise impacts on cell fate and cell behavior