Cardiac Mitogen Signaling During Zebrafish Heart Regeneration

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2020

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Abstract

Adult zebrafish demonstrate a remarkable capacity to regenerate heart tissue following injury, and thus have served as a valuable model for developing our understanding of cardiac repair and regeneration. Recent work has identified and characterized multiple cardiac mitogens all of which can drive cardiomyocyte (CM) division in the absence of injury. Despite these impressive responses, little is known regarding the shared specific molecular mechanisms of CM proliferation that lie downstream of these unique ligand-receptor interactions. Here, we found that the tumor suppressor p53 was significantly suppressed during regeneration which correlated with increases in the transcription of p53’s primary negative regulator Mdm2. Using established and newly generated transgenic lines we demonstrated that experimentally altering cellular p53 levels affects CM proliferation. Inducible overexpression of the cardiac mitogens Nrg1 and Vegfaa demonstrated similar findings with increased mdm2 transcription and p53 suppression during regeneration along with augmented CM proliferation with loss of p53. Furthermore, we observed significant overlap between gata4 and mdm2 gene expression domains during development, following heart injury, and with mitogen stimulation suggesting potential interactions between these two genes.  Our findings indicate a novel injury and mitogen-induced function of Mdm2 to repress p53 during zebrafish heart regeneration. Here we also investigated the presence of additional cardiac mitogens, specifically HB-EGF, an ErbB ligand. We found that both HB-EGF paralogs are both present in the zebrafish heart and are both transcriptionally upregulated near the site of injury. A newly generated set of novel HB-EGF transgenic reporters, knock-outs, and overexpression lines will further investigate the importance of these early findings and HB-EGF signaling which will add to our understanding of heart regeneration.

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Shoffner, Adam (2020). Cardiac Mitogen Signaling During Zebrafish Heart Regeneration. Dissertation, Duke University. Retrieved from https://hdl.handle.net/10161/22161.

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