Disruption of MEF2 activity in cardiomyoblasts inhibits cardiomyogenesis.
Myocyte enhancer factors (MEF2s) bind to muscle-specific promoters and activate transcription. Drosophila Mef2 is essential for Drosophila heart development, however, neither MEF2C nor MEF2B are essential for the early stages of murine cardiomyogenesis. Although Mef2c-null mice were defective in the later stages of heart morphogenesis, differentiation of cardiomyocytes still occurred. Since there are four isoforms of MEF2 factors (MEF2A, MEF2B, MEF2C and MEF2D), the ability of cells to differentiate may have been confounded by genetic redundancy. To eliminate this variable, the effect of a dominant-negative MEF2 mutant (MEF2C/EnR) during cardiomyogenesis was examined in transgenic mice and P19 cells. Targeting the expression of MEF2C/EnR to cardiomyoblasts using an Nkx2-5 enhancer in the P19 system resulted in the loss of both cardiomyocyte development and the expression of GATA4, BMP4, Nkx2-5 and MEF2C. In transiently transgenic mice, MEF2C/EnR expression resulted in embryos that lacked heart structures and exhibited defective differentiation. Our results show that MEF2C, or genes containing MEF2 DNA-binding sites, is required for the efficient differentiation of cardiomyoblasts into cardiomyocytes, suggesting conservation in the role of MEF2 from Drosophila to mammals.
Karamboulas
Christina
C
Department of Biochemistry, Medical Sciences Building, University of Western Ontario, London, Ontario, N6A 5C1, Canada.
Dakubo
Gabriel D
GD
Liu
Jun
J
De Repentigny
Yves
Y
Yutzey
Katherine
K
Wallace
Valerie A
VA
Kothary
Rashmi
R
Skerjanc
Ilona S
IS
D000818:Animals; D001665:Binding Sites; D015152:Blotting, Northern; D002449:Cell Aggregation / Q000235:genetics / Q000502:physiology; D002454:Cell Differentiation / Q000235:genetics / Q000502:physiology; D045744:Cell Line, Tumor; D005260:Female; D050991:GATA4 Transcription Factor / Q000235:genetics / Q000378:metabolism; D000072576:Homeobox Protein Nkx-2.5; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D017403:In Situ Hybridization; D064326:MEF2 Transcription Factors; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008954:Models, Biological; D024510:Muscle Development / Q000235:genetics* / Q000502:physiology; D009206:Myocardium / Q000166:cytology / Q000378:metabolism; D018006:Myogenic Regulatory Factors / Q000235:genetics* / Q000378:metabolism / Q000502:physiology; D011485:Protein Binding; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
D050991:GATA4 Transcription Factor; D000072576:Homeobox Protein Nkx-2.5; D018398:Homeodomain Proteins; D064326:MEF2 Transcription Factors; C578041:Mef2c protein, mouse; D018006:Myogenic Regulatory Factors; C484469:Nkx2-5 protein, mouse; D014157:Transcription Factors