Ddx61-enriched condensates refine heart regeneration programs

Gene regulatory mechanisms that underlie tissue regeneration have been largely studied at the level of transcription. Here, proximity labeling methods identify increased presence of the RNA helicase and P-body marker Ddx61 in adult zebrafish cardiomyocytes induced to divide by injury or mitogens. Ddx61 molecules form complex condensates in cardiomyocytes during cardiogenic settings in zebrafish, developing mice, and cultured human cells. ddx61 mutations disrupt cardiomyocyte proliferation and heart regeneration indices in adult zebrafish, and DDX6 knockdown reduces proliferation of cultured human cardiomyocytes. During heart regeneration, Ddx61 associates with and is required to restrain expression of mRNA encoding Chordin, a secreted BMP inhibitor that impedes regeneration if present at high levels. Our experiments indicate that mRNA sorting by context-dependent condensates can impact tissue regenerative capacity.