Organogenesis begins with the specification of the appropriate quantity and variety of organ progenitor cells. During heart development, the generation of specific numbers and types of progenitor cells is necessary for the formation of cardiac chambers of the appropriate size and characteristics. In its simplest form, the embryonic vertebrate heart is composed of two major chambers, a ventricle and an atrium. Ventricular and atrial cardiomyocytes differ morphologically, histologically, and physiologically. The intrinsic differences between chambers are critical for effective cardiac function, but the mechanisms responsible for production of the correct numbers of ventricular and atrial cardiomyocytes are not well understood. The long-term goal of our research is to identify the genetic pathways that regulate two crucial aspects of cardiomyocyte production: the specification of a proper number of cardiac progenitors and their allocation into ventricular and atrial populations. Using the zebrafish as a model organism, we have assembled a collection of mutations that disrupt cardiomyocyte production. Additionally, we have established high- resolution fate mapping techniques capable of distinguishing whether and how specific genes regulate cardiac fate assignment. This combination of approaches has yielded several insights regarding the mechanisms that define and divide the cardiac progenitor pool. Most notably, we have discovered an essential early function of retinoic acid (RA) signaling. Reduction of RA signaling produces an excess of cardiomyocytes, via fate transformations that increase the number of cardiac progenitor cells. Thus, RA has a potent repressive role during cardiac specification. Here, we propose to delve deeper into the repressive influence of RA signaling and to investigate an independent pathway with a previously undescribed role in restricting cardiac specification. Additionally, we will broaden our scope to include the analysis of signaling pathways hypothesized to control the relative proportions of ventricular and atrial progenitors.
Our specific aims are: (1) to determine how RA signaling restricts cardiac specification, (2) to demonstrate how endothelial and myeloid specification pathways repress cardiac developmental potential, (3) to test the role of Bmp signaling in promoting atrial cardiomyocyte production, and (4) to identify the roles of Fgf signaling during ventricular cardiomyocyte production. Together, these studies will illuminate new features of the network of pathways controlling cardiomyocyte production. In the long term, this information will improve our understanding of the causes of common cardiac birth defects and suggest strategies for the therapeutic manipulation of cardiac stem cells.
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