The interaction of anabolic mTOR signaling and catabolic autophagic activity during zebrafish heart regeneration

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In contrast to mammals, zebrafish can regenerate the heart via proliferation of cardiomyocytes and complete resorption of transient scar tissue. Macrophage infiltration and revascularization of the wound, which happen early after injury, are essential for subsequent cardiomyocyte regeneration. However, little is known about the molecular regulation of these early injury responses and how they are linked with injury responses in cardiomyocytes. We have discovered that mechanistic target of rapamycin (mTOR) signaling is activated in zebrafish wound border cardiomyocytes within 1 day after heart injury, as well as in infiltrating leukocytes and in endothelial cells. Interference with mTOR signaling shows that the pathway is required for cardiomyocyte proliferation and morphological heart regeneration. Our preliminary results thus define mTOR signaling activation as one of the earliest known responses of zebrafish cardiomyocytes to heart injury and they suggest important functions for mTOR signaling in early injury responses of other cell types as well. Using genetic, pharmacological and biochemical tools we will elucidate the role of mTOR signaling in neutrophil and macrophage infiltration, wound revascularization and cardiomyocyte dedifferentiation.While the mTOR pathway activates anabolism, it inhibits autophagy, which has catabolic functions, in many systems. Surprisingly, we found that autophagy is activated in wound border cardiomyocytes in injured zebrafish hearts, and that inhibition of autophagic flux results in cardiomyocyte proliferation defects and failure of morphological regeneration. This suggests that anabolic mTOR signaling and catabolic autophagic activity need to be tightly balanced for successful heart regeneration. We will study whether autophagy is required for cardiomyocyte dedifferentiation and how mTOR signaling and autophagy interact in wound border cardiomyocytes.Together, the experiments in this proposal will shed light on the molecular regulation of early injury responses in zebrafish heart regeneration.