Cardiac compensation in ErbB2‐deficient zebrafish embryos

During heart development, the heart chambers undergo dramatic changes in chamber topology, most notably the formation of luminal, muscular protrusions called trabeculae. While altered trabeculation is associated with many congenital heart diseases, complete failure to form trabeculae results in embryonic lethality across different species. We have previously reported that ErbB2 signaling is required for cardiac trabeculation. Although erbb2 mutant hearts do not exhibit any functional defects initially, these hearts develop progressive cardiac dysfunction with reduced fractional shortening, and eventually fail. However, the mechanism underlying this functional deterioration in the absence of trabecular formation is not known. Using zebrafish as a model, we found that inhibition of ErbB2 activity pharmacologically and genetically to block cardiac trabeculation resulted in an increase in ventricular cardiomyocyte cross‐sectional area and myofibril size. This cardiac phenotype is reminiscent of hypertrophic growth of an adult heart subjected to mechanical overload. Consistently, we found that the expression of nppa, a hypertrophic marker gene, was elevated in erbb2 mutants compared to controls. In addition, inhibition of Target of Rapamycin (TOR) signaling by rapamycin treatment suppressed erbb2 mutant hypertrophic growth phenotype, suggesting that hypertrophy of erbb2 mutant hearts occurs in an mTOR‐dependent manner. Taken together, we propose that trabeculae may play a role in optimizing chamber topology for efficient cardiac function. Support or Funding Information National Science Foundation Graduate Research Fellowship (NSF‐GRF): DGE‐1144081