Ruvbl2 Is a Negative Regulator of Zebrafish Cardiomyocyte Proliferation
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CitationSharpe, Michka. 2020. Ruvbl2 Is a Negative Regulator of Zebrafish Cardiomyocyte Proliferation. Doctoral dissertation, Harvard University, Graduate School of Arts & Sciences.
AbstractIn contrast to mammals, which are unable to regenerate their hearts, the zebrafish is capable of heart regeneration through robust proliferation of pre-existing cardiomyocytes. The mechanisms that regulate the regenerative discrepancy between zebrafish and mammals remain largely unknown. In this thesis, we explore the genetic programs that govern cardiomyocyte proliferation in zebrafish during embryogenesis and regeneration, as well as the genetic programs that influence their cardiomyocyte DNA content. First, we find that fosl2, while a critical regulator of second heart field myocardial accretion and ventricular chamber formation, is not essential for regeneration. Additionally, we demonstrate that the evolutionarily conserved innate immune receptor, c5ar1, is required for cardiomyocytes to proliferate and regenerate after injury. Furthermore, we find that experimental induction of polyploidization in zebrafish cardiomyocytes is sufficient to block regeneration after injury. Finally, we demonstrate that ruvbl2 is a negative regulator of cardiomyocyte proliferation in the zebrafish embryo. Interestingly, we find that myocardial or endocardial overexpression of ruvbl2 is sufficient to suppress cardiomyocyte proliferation, demonstrating both the autonomous and non- autonomous role of ruvbl2 in regulating cardiomyocyte proliferation during cardiac growth. After cardiac injury during adulthood, we find that cardiomyocyte-specific overexpression of ruvbl2 is sufficient to dampen the cardiomyocyte proliferative response and leads to scar formation. Taken together, these studies provide a robust framework with which to dissect the molecular mechanisms that regulate cardiomyocyte proliferation during embryogenesis and adulthood, as well as a means to understand the role of cardiomyocyte ploidy during regeneration after injury. Collectively, these data bolster our understanding of cardiac regeneration, allowing for the development of novel therapeutic strategies to enhance proliferation of cardiomyocytes in patients after myocardial infarction.
Citable link to this pagehttps://nrs.harvard.edu/URN-3:HUL.INSTREPOS:37365520
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