Constructing an organ is an elaborate process that is not well understood. What mechanisms drive cells to attain the appropriate position and shape within an organ? How do different cell types within an organ interact during morphogenesis? These questions can be addressed in the context of the heart, which undergoes elaborate morphogenesis to rearrange bilateral populations of myocardial and endocardial precursor cells into a highly specialized multi-chambered organ. Heart shape relies on proper cell movements during early morphogenesis, when both cell types organize to form a two-layered heart tube consisting of an outer myocardium and an inner endocardium. Thus it is of interest to elucidate the mechanisms underlying the process of heart tube formation. This is particularly pertinent to understanding the causes of congenital heart defects, many of which are a result of failure to arrange cardiac cells properly during early heart morphogenesis. The goal of my postdoctoral research is to take advantage of the zebrafish as a model system to elucidate key components of the cellular and genetic regulation responsible for heart tube assembly. The zebrafish is an ideal system in which to study cardiac cell movements due to the easy visualization of the heart, the availability of transgenes appropriate for high-resolution time-lapse imaging, and the options for manipulating gene function through loss- and gain-of-function approaches. Previous work in the Yelon lab has discovered some of the fundamental cellular behaviors and genes required for myocardial precursor migration towards the midline. Following migration, cardiomyocytes coalesce around the endocardium to form a shallow cone, which then extends to form the linear heart tube. Little is known about the cellular and molecular mechanisms driving heart tube extension. Based on my preliminary studies, I hypothesize that myocardial cells undergo mediolateral intercalations to drive extension, and that the planar cell polarity pathway plays a role in orchestrating myocardial tube extension. The regulation of endocardial tube extension may be quite different, as endothelial tube assembly relies on precise control of cell-cell contacts. My preliminary data suggest that, during endocardial morphogenesis, cells begin directional migration as individuals followed by formation of cell-cell junctions, and that VEcadherin plays a role in this process. I will test these hypotheses through the following specific aims: 1) Determining the cell behaviors driving myocardial and endocardial tube extension, 2) Determining the role of planar cell polarity in myocardial tube extension and the role of VE-cadherin in endocardial tube extension, and 3) Conducting a chemical genetic screen to identify new regulators of heart tube extension.
| Schumacher, Jennifer A; Bloomekatz, Joshua; Garavito-Aguilar, Zayra V et al. (2013) tal1 Regulates the formation of intercellular junctions and the maintenance of identity in the endocardium. Dev Biol 383:214-26 |
