Targoff, K.L., Colombo, S., George, V., Schell, T., Kim, S.H., Solnica-Krezel, L., and Yelon, D. (2013) Nkx genes are essential for maintenance of ventricular identity. Development (Cambridge, England). 140(20):4203-4213.
Establishment of specific characteristics of each embryonic cardiac chamber is crucial for development of a fully functional
adult heart. Despite the importance of defining and maintaining unique features in ventricular and atrial cardiomyocytes,
the regulatory mechanisms guiding these processes are poorly understood. Here, we show that the homeodomain transcription
factors Nkx2.5 and Nkx2.7 are necessary to sustain ventricular chamber attributes through repression of atrial chamber identity.
Mutation of nkx2.5 in zebrafish yields embryos with diminutive ventricular and bulbous atrial chambers. These chamber deformities emerge gradually
during development, with a severe collapse in the number of ventricular cardiomyocytes and an accumulation of excess atrial
cardiomyocytes as the heart matures. Removal of nkx2.7 function from nkx2.5 mutants exacerbates the loss of ventricular cells and the gain of atrial cells. Moreover, in these Nkx-deficient embryos,
expression of vmhc, a ventricular gene, fades, whereas expression of amhc, an atrial gene, expands. Cell-labeling experiments suggest that ventricular cardiomyocytes can transform into atrial cardiomyocytes
in the absence of Nkx gene function. Through suggestion of transdifferentiation from ventricular to atrial fate, our data
reveal a pivotal role for Nkx genes in maintaining ventricular identity and highlight remarkable plasticity in differentiated
myocardium. Thus, our results are relevant to the etiologies of fetal and neonatal cardiac pathology and could direct future
innovations in cardiac regenerative medicine.