Analysis of the role for hedgehog signaling in cardiac progenitor specification.

摘要

The embryonic heart originates from the specification and subsequent differentiation of cardiac progenitors. Cardiac progenitors are specified within heart fields, territories of the embryo where uncommitted multipotent cells receive the inductive and repressive signals that control cardiac specification. Providing that the correct balance of signaling is received, populations consisting of the appropriate types and numbers of cardiac progenitors emerge from the heart fields. While multiple signaling pathways have been implicated in cardiac specification, the entire collection of signals required for its optimal execution remain unknown.;My thesis research sought to define the role of the Hedgehog signaling pathway in cardiac specification in the zebrafish. I found that Hedgehog signaling plays an early and direct role in promoting cardiac specification. In the zebrafish embryo, reducing Hh signaling via genetic or pharmacological means creates a cardiomyocyte deficit, and increasing Hh signaling creates a cardiomyocyte surplus. Time course studies show that Hedgehog signaling is required from the start of gastrulation through early somitogenesis for cardiomyocyte formation. Fate mapping indicates that fewer cardiac progenitors are specified in the absence of Hedgehog signaling. Genetic inducible fate mapping in mouse indicates that myocardial progenitors directly respond to Hh signals. Transplantation experiments in zebrafish demonstrate that Hh signaling acts cell autonomously to promote the contribution of cells to the myocardium. Combined, these data indicate that Hedgehog signaling is required by myocardial progenitors for optimal cardiomyocyte generation.;Cardiac regenerative medicine is a growing field that seeks to utilize cell-based therapeutic intervention to improve or restore cardiac function to diseased or injured hearts. Effectively harnessing the potential for stem cells to form cardiomyocytes is a major goal of the field, one that requires an understanding of the endogenous process of cardiac fate specification and differentiation. My studies, which indicate an early role for the Hedgehog signaling pathway in cardiac specification, suggest that manipulation of this pathway could facilitate achieving the goals of such regenerative therapies.