Popeye domain containing 1 (Popdc1) is a member of the POPDC gene family, which code for membrane proteins abundantly expressed in heart and skeletal muscle. They bind cAMP and are thought to function as effector proteins involved in stress signalling. popdc1 null mutant zebrafish have been created using TALENs to cause a premature stop codon resulting in a heavily truncated and non-functional peptide being translated. These mutants survive embryogenesis and larval development and so here I begin to characterise the adults.
Popdc1 null mutants displayed abnormal outflow tracts and heart positioning which may cause cardiac stress. It was also observed that cardiomyocyte size is reduced and heart size is increased in mutants, which could result from cardiac remodelling because of stressors such as pressure overload. Moreover, mutants had a thickened cortical layer and reduced trabecular complexity which may lead to improper heart function. Single nuclear RNA sequencing (snRNA-seq) data show a reduction in presumptive trabecular cardiomyocytes and a unique population of hyper-stressed cardiomyocytes which could explain the morphological differences in the mutant. This data also showed popdc1 null mutant cardiomyocytes had abnormalities in genes involved in energy metabolism and cardiac regeneration including fstl1b, tbx5a and runx1.
When heart regeneration was tested, mutants displayed reduced regenerative capacity and cardiomyocyte proliferation. Ploidy was also increased in mutant cardiomyocytes, a factor known to hinder cardiomyocyte proliferation. However, this was contrary to the negative regulatory effect that the POPDC proteins have on the proto-oncogene, c-Myc, which would have predicted that the loss of popdc1 would enhance regeneration.
Overall, the adult popdc1 null mutant hearts have several morphological phenotypes which are likely caused by or the cause of a hyper-stressed population of cardiomyocytes. High stress along with other factors is also likely to cause the reduced regenerative capacity observed in the mutants.