Palencia-Desai, S., Kohli, V., Kang, J., Chi, N.C., Black, B.L., and Sumanas, S. (2011) Vascular endothelial and endocardial progenitors differentiate as cardiomyocytes in the absence of Etsrp/Etv2 function. Development (Cambridge, England). 138(21):4721-4732.
Previous studies have suggested that embryonic vascular endothelial, endocardial and myocardial lineages originate from multipotential
cardiovascular progenitors. However, their existence in vivo has been debated and molecular mechanisms that regulate specification
of different cardiovascular lineages are poorly understood. An ETS domain transcription factor Etv2/Etsrp/ER71 has been recently
established as a crucial regulator of vascular endothelial differentiation in zebrafish and mouse embryos. In this study,
we show that etsrp-expressing vascular endothelial/endocardial progenitors differentiate as cardiomyocytes in the absence of Etsrp function
during zebrafish embryonic development. Expression of multiple endocardial specific markers is absent or greatly reduced in
Etsrp knockdown or mutant embryos. We show that Etsrp regulates endocardial differentiation by directly inducing endocardial
nfatc1 expression. In addition, Etsrp function is required to inhibit myocardial differentiation. In the absence of Etsrp function,
etsrp-expressing endothelial and endocardial progenitors initiate myocardial marker hand2 and cmlc2 expression. Furthermore, Foxc1a function and interaction between Foxc1a and Etsrp is required to initiate endocardial development,
but is dispensable for the inhibition of myocardial differentiation. These results argue that Etsrp initiates endothelial
and endocardial, and inhibits myocardial, differentiation by two distinct mechanisms. Our findings are important for the understanding
of genetic pathways that control cardiovascular differentiation during normal vertebrate development and will also greatly
contribute to the stem cell research aimed at regenerating heart tissues.