Organ-Level Communication During Heart Regeneration In Zebrafish.

Abstract

<p>Tissue regeneration has been primarily investigated as local remodeling events in response to tissue damage or loss. Recent studies, however, indicate that uninjured structures can respond to distant tissue trauma and, in some cases, regulate tissue regeneration. One of the key questions that haven’t been answered in the field is how animals simultaneously exert customized control of local and remote injury responses during regeneration. Taking advantage of the genetic cardiomyocyte ablation system developed in adult zebrafish, we explored uninjured brain and kidney responses to heart regeneration. This dissertation identified a transcription factor gene, cebpd, through transcriptomic profiling of the uninjured brain and kidney during zebrafish heart regeneration. The expression of cebpd is induced both locally in the epicardial tissue of regenerating hearts and distantly in the brain ependymal layer and renal tubules. Knocking out cebpd using the CRISPR system, we found that cebpd is required for tissue repair adjacent to an injury event, as well as in the physiological sequelae of fluid regulation encompassing remote tissues. By profiling and molecular genetics in zebrafish, we identified a novel class of remote tissue regenerative enhancer elements (r-TREEs) responsible for remote gene activation during tissue regeneration. Interestingly, removing cebpd associated enhancer element CEN only abolished gene activation in remote uninjured brain and kidney but not local regenerating hearts. We further demonstrated that corticosteroid receptor activities are sufficient and required for CEN-dependent regulation of gene expression in remote tissues during regeneration. Loss of CEN perturbed fluid regulation in zebrafish during heart regeneration. My findings suggest a novel concept in tissue regeneration, in which r-TREEs segregate local and remote responses and stratify regeneration and physiological functions of key regulatory genes to achieve whole-organism coordination during regeneration.</p>