Tuesday, April 23, 2024
4/23/2024
PROJECT SUMMARY Organ development requires the precise allocation of specified cell types committed to distinct lineages with specialized roles and morphology that directly relate to organ function. As such, organ health is dependent on the maintenance of cellular diversity within the tissue. During heart development, for example, cardiac progenitors mature into chamber-specific cardiomyocytes characterized by unique molecular signatures. As the heart is one of the first organs to form and function in the embryo, atrial cardiomyocyte (ACM) and ventricular cardiomyocyte (VCM) precursors are specified and spatially segregated at an early stage of development. After this initial specification, however, ACMs and VCMs require sustained signals to reinforce their chamber-specific identity. Research in multiple model organisms has uncovered a period of cardiomyocyte plasticity in which ACMs and VCMs can alter their chamber-specific characteristics in the absence of key transcription factors or after modifications to important signaling pathways. Recent work by our laboratory has shown in zebrafish that the FGF signaling pathway is required upstream of Nkx transcription factors to enforce VCM identity. However, it remains unknown if other factors cooperate or compete with FGF signaling to promote VCM maintenance. Our preliminary studies suggest two potent influences on the maintenance of VCM identity that have not been previously studied in this context: (1) the inhibition of BMP signaling, and (2) endocardial-myocardial signaling. Inspired by these findings, I propose a model in which opposition between BMP and FGF signaling in the myocardium cooperates with an unidentified endocardial cue to reinforce VCM commitment. To test this model, I have designed a series of approaches that will employ loss-of-function and gain-of-function studies, mosaic analysis, and epistasis experiments. The findings from this proposal will uncover novel insights into the relationship between BMP, FGF and endocardial-myocardial signaling in the context of VCM maintenance. Moreover, my proposed studies promise to elevate the current understanding of how cardiomyocytes remain committed to chamber-specific lineages. Examining the mechanisms that maintain cardiac chamber identity in differentiated cells may illuminate the causes of certain congenital heart diseases as well as provide targets for regenerative medicine and therapeutic approaches.
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