Abnormalities in the formation and/or function of the embryonic heart often lead to embryonic lethality or severe health problems later in life. Understanding the fundamental mechanisms underlying early heart development at the cellular and molecular level is not only scientifically challenging but is also clinically relevant. We choose the zebrafish as our model organism to study early cardiac patterning because it is amenable to genetic, embryological and molecular manipulation. Furthermore, the embryonic hearts of all vertebrate species undergo similar morphogenic processes and are regulated by conserved genetic circuits. Information obtained from one model organism may apply to other vertebrates, including humans. In this project, we take three independent approaches to study the cellular and molecular mechanisms governing primitive heart tube morphogenesis. Our recent study on the zebrafish heart and mind mutation uncovered an unexpected role of Na,K-ATPase a1B1 in the elongation of the primitive heart tube. We will investigate the impact of loss of function of Na,K-ATPase a1 B1 on the cellular architecture of cardiomyocytes. We will also investigate the interaction of Na,K-ATPase a1 B1 other genes critical for the morphogenesis of the primitive heart tube in zebrafish at the cellular and genetic level (Aim 1). Furthermore we will investigate the molecular mechanism by which the Na,K-ATPase a1 B1 regulates the elongation of the primitive heart tube in the zebrafish and in cultured cells, as the first step toward understanding genetic networks involved in the primitive heart tube formation (Specific Aim 2). Finally, from an ongoing zebrafish genetic screen, we identified a new mutation affecting the patterning of the primitive heart tube. We will characterize the phenotypes of this mutant and identify the molecular lesion causing this mutant phenotype (Aim 3). The combination of cellular, molecular and genetic studies proposed in this project will provide new and in-depth insight into mechanisms of primitive heart tube morphogenesis. ? ? ?
