Organogenesis requires the specification of diverse cell fates, coordinated cellular movements, cell shape changes, and cellular interactions to generate a properly formed and functioning organ. Vertebrate heart formation begins as bilateral sheets of myocardial precursors move toward the embryonic midline, where they converge and surround the central endocardial core, to form a cardiac ring. Subsequently, the cardiac ring elongates into a simple linear heart tube composed of a set of nested cylinders;the inner endothelial endocardium endocardium and overlying muscular myocardium myocardium. Interactions between these two layers instruct the morphological and physiological properties of both layers during both linear heart tube formation and later cardiac maturation. Because the linear heart tube serves as a scaffold for all further cardiac maturation, even small errors in these endocardium endocadrial/myocardial interactions can have grave consequences on cardiac function and thus survival. Unfortunately, the cellular and molecular basis of endocardial/myocardial interactions during linear heart tube formation is poorly characterized. Our recent work has demonstrated a requirement for early interactions between these thwo tissues in regulating the directed cell migration of the myocardium during cardiac ring formation. In addition, we have identified a morphologically distinct flk1/kdrb positive, fli-1 negative subpopulation of endocardial cells we call the endocardial ring juxtaposed to the myocardium at cardiac ring stage. Loss of these cells results in the formation of a dismorphic cardiac ring and heart tube defects. Based on this preliminary data, We hypothesize that a newly identified VEGF receptor expressing endocardial subpopulation directs the formation of the myocardial ring, a key step in heart tube assembly that acts as a scaffold for myocardial elongation. To test this hypothesis, I propose to: 1) Assess the requirement for VEGFR in formation the of endocardial ring. 2) Test the requirement for the endocardial ring in directing heart tube assembly. 3) Investigate the role of the endocardial ring in directing heart tube elongation. Understanding the role of the genetic interactions between endocardium and myocardium in regulating the cell behaviors driving cardiac morphogenesis is a crucial first step in understanding heart tube assembly and elongation.
One in ten still born babies and one in a hundred live births have congenital heart defects. Understanding the molecular regulation of early heart formation is a crucial first step in understanding the basis of these devastating conditions. In this proposal we plan to examine interactions between two of the layers of the heart, the myocardium and the endocardium. We believe that these interactions play a key role in regulating myocardial movement and that understanding them will help to defining the molecular control of cell movement and ultimately proper heart formation.
| Lenhart, Kari F; Holtzman, Nathalia G; Williams, Jessica R et al. (2013) Integration of nodal and BMP signals in the heart requires FoxH1 to create left-right differences in cell migration rates that direct cardiac asymmetry. PLoS Genet 9:e1003109 |
