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.
Papadimou
Evangelia
E
CRBM, CNRS FRE 2593, Montpellier, France.
Ménard
Claudine
C
Grey
Corinne
C
Pucéat
Michel
M
D000818:Animals; D002454:Cell Differentiation / Q000502:physiology*; D019070:Cell Lineage / Q000502:physiology; D002868:Chromosomal Proteins, Non-Histone / Q000172:deficiency / Q000378:metabolism*; D051379:Mice; D008840:Microfilament Proteins; D009200:Myocardial Contraction; D009206:Myocardium / Q000166:cytology*; D032383:Myocytes, Cardiac / Q000166:cytology* / Q000378:metabolism; D041681:NIH 3T3 Cells; D016160:Retinoblastoma Protein / Q000172:deficiency / Q000378:metabolism / Q000502:physiology*; D013234:Stem Cells / Q000166:cytology / Q000502:physiology*
D002868:Chromosomal Proteins, Non-Histone; D008840:Microfilament Proteins; D016160:Retinoblastoma Protein; C094772:centromere protein F