Organ function relies upon the appropriate attributes of each of its individual operational components. For example, in the embryonic vertebrate heart, effective propulsion of circulation depends upon the distinct morphological, electrophysiological, and contractile traits of the atrial and ventricular chambers. Despite centuries of awareness of the key differences between atrial and ventricular cardiomyocytes, the fundamental mechanisms that allocate cells into chamber-specific lineages and direct chamber-specific differentiation remain largely mysterious. Our laboratory's research focuses on understanding the genetic pathways responsible for chamber fate assignment. By exploiting the utility of the zebrafish as a model organism, we have shown that the BMP and FGF signaling pathways differentially affect atrial and ventricular cell numbers, providing important clues to the mechanisms that initially establish the atrial and ventricular progenitor pools. Furthermore, our preliminary data indicate that initial chamber fate decisions can be plastic and that mechanisms exist to maintain chamber- specific characteristics in differentiated myocardium. Together, our studies suggest an intriguing model in which early patterning of the heart field, followed by later reinforcement of chamber identity, results in proper chamber fate assignment. Here, we propose to evaluate aspects of this model in detail.
In Aim 1, we will delve deeper into the mechanisms responsible for the initial establishment of chamber progenitor pools. Specifically, we will use fate mapping, time-lapse tracking, mosaic analysis, and evaluation of candidate effector genes to determine how BMP signaling promotes the establishment of atrial progenitor cells.
In Aim 2, we will investigate the mechanisms that maintain chamber identity. Employing transgenic reporters of chamber identity, time-lapse analysis, mosaic analysis, and dissection of chamber-specific regulatory sequences, we will test whether FGF signaling functions to insure maintenance of ventricular chamber identity by promoting expression of nkx genes. Finally, in Aim 3, we will pursue identification of new pathways that regulate chamber fate assignment, taking advantage of our discovery of 4 intriguing compounds that impact atrial or ventricular cardiomyocyte production. Together, our studies will illuminate new features of the network of pathways controlling chamber fate assignment. In the long term, this work has the potential to shed light on the causes of cardiac birth defects and to facilitate innovations in regenerative medicine.
Effective heart function depends upon the specific dimensions and functional characteristics of the atrial and ventricular cardiac chambers. However, the genetic pathways responsible for creating distinct atrial and ventricular tissues are not well understood. In the long term, a better comprehension of this topic will improve our understanding of the causes of common cardiac birth defects and will suggest strategies for directing chamber-specific differentiation of pluripotent cells for therapeutic purposes.
|Schindler, Yocheved L; Garske, Kristina M; Wang, Jinhu et al. (2014) Hand2 elevates cardiomyocyte production during zebrafish heart development and regeneration. Development 141:3112-22|
|Schumacher, Jennifer A; Bloomekatz, Joshua; Garavito-Aguilar, Zayra V et al. (2013) tal1 Regulates the formation of intercellular junctions and the maintenance of identity in the endocardium. Dev Biol 383:214-26|
|Targoff, Kimara L; Colombo, Sophie; George, Vanessa et al. (2013) Nkx genes are essential for maintenance of ventricular identity. Development 140:4203-13|
|Miura, Grant I; Yelon, Deborah (2011) A guide to analysis of cardiac phenotypes in the zebrafish embryo. Methods Cell Biol 101:161-80|
|Waxman, Joshua S; Yelon, Deborah (2011) Zebrafish retinoic acid receptors function as context-dependent transcriptional activators. Dev Biol 352:128-40|
|Evans, Sylvia M; Yelon, Deborah; Conlon, Frank L et al. (2010) Myocardial lineage development. Circ Res 107:1428-44|
|Feng, L; Hernandez, R E; Waxman, J S et al. (2010) Dhrs3a regulates retinoic acid biosynthesis through a feedback inhibition mechanism. Dev Biol 338:1-14|
|Waxman, Joshua S; Yelon, Deborah (2009) Increased Hox activity mimics the teratogenic effects of excess retinoic acid signaling. Dev Dyn 238:1207-13|
|Marques, Sara R; Yelon, Deborah (2009) Differential requirement for BMP signaling in atrial and ventricular lineages establishes cardiac chamber proportionality. Dev Biol 328:472-82|
|Mich, John K; Blaser, Heiko; Thomas, Natalie A et al. (2009) Germ cell migration in zebrafish is cyclopamine-sensitive but Smoothened-independent. Dev Biol 328:342-54|
Showing the most recent 10 out of 18 publications