Delineating the Role of FGF Signaling and Vertebrate Heart Development

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DESCRIPTION (provided by applicant): Congenital heart defects are one of the most common genetic anomalies, and is the leading cause of deaths in infants. The biology of how cardiac progenitor cells become the first functional organ in the embryo is therefore an important process to resolve. The cardiac progenitor cells are initially specificed very early in development as two populations of cells within the embryo that later migrate and to meet at the midline and form the heart tube. Eventually through a process known as morphogenesis this population of cells evolve to build a functional heart that provides the pump for nutritional and waste exchange in the embryo. This proposal aims to elucidate the role for the Fibroblast Growth Factor signaling (FGF) and (ETS) transcription factors in heart formation. FGFs have been implicated to play an important role in heart formation and mutations in components of this signaling pathway that alter cellular communication during embryogenesis are the cause of human genetic disease, that often includes cardiac defects. We will test the hypothesis that FGFs and ETS factors are required during the earliest phases of cardiac progenitor specification (Aim 1). More important we will determine the mechanism of gene regulation by FGFs and Ets factors (Aim 2). Further, we have identified a small molecule that hyperactives FGF signaling in the embryo and future studies will determine its affects on cardiac development (Aim 3). Understanding how FGFs can alter cell fate and the genes that they control to achieve this is a fundamental question of how cells are molded into organs. This proposal will combine the embryological and genetic features of the zebrafish embryo to answer these questions. PUBLIC HEALTH RELEVANCE. The manual for heart formation is written in as a set of detail instructions encoded in the DNA. How these instructions are read and implemented by cells that eventually become a functional beating organ is the focus of this proposal. Specifically the goal is to understand how a family of ETS transcriptional factors can direct cardiac development in the zebrafish. Another goal related to heart development is the idea that chemical compounds can be used to influence heart growth and differentiation. To reach this goal, we have developed a zebrafish biosensor that can report on signaling activity and have identified a small molecule that can expand cardiac progenitors during development. Understanding how this molecule acts to increase heart tissue is an important step towards developing potential treatment for cardiac damage caused by heart disease.