Interplay between the retinoblastoma protein and LEK1 specifies stem cells toward the cardiac lineage

The molecular mechanisms governing early cardiogenesis are still largely unknown. Interestingly, the retinoblastoma protein (Rb), a regulator of cell cycle, has recently emerged as a new candidate regulating cell differentiation. Rb−/− mice die at midgestation and mice lacking E2f1/E2f3 , downstream components of the Rb‐dependent transcriptional pathway, die of heart failure. To gain insight into the function of Rb pathway in early cardiogenesis, we used Rb−/− embryonic stem (ES) cells differentiating into cardiomyocytes. Rb−/− cells displayed a dramatic delay in expression of cardiac‐specific transcription factors and in turn in the whole process of cardiac differentiation. The phenotype of Rb−/− ES cell‐derived cardiomyocytes was rescued by reintroducing Rb in cardiac progenitors, by stimulating the BMP‐dependent cardiogenic pathway or by overexpression of Nkx2.5. ES cells deficient in the recently identified factor LEK1, a murine homolog of the cardiomyogenic factor 1, or specific disruption of Rb–LEK1 interaction into the nucleus of differentiating ES cells recapitulated the delay in cardiac differentiation of Rb−/− ES cells. Thus, we provide evidence for a novel Rb/LEK1‐dependent and BMP‐independent transcriptional program, which plays a pivotal role in priming ES cells toward a cardiac fate.