Cooperative interaction of Nkx2.5 and Mef2c transcription factors during heart development.
The interactions of diverse transcription factors mediate the molecular programs that regulate mammalian heart development. Among these, Nkx2.5 and the Mef2c regulate common downstream targets and exhibit striking phenotypic similarities when disrupted, suggesting a potential interaction during heart development. Co-immunoprecipitation and mammalian two-hybrid experiments revealed a direct molecular interaction between Nkx2.5 and Mef2c. Assessment of mRNA expression verified spatiotemporal cardiac coexpression. Finally, genetic interaction studies employing histological and molecular analyses showed that, although Nkx2.5(-/-) and Mef2c(-/-) individual mutants both have identifiable ventricles, Nkx2.5(-/-);Mef2c(-/-) double mutants do not, and that mutant cardiomyocytes express only atrial and second heart field markers. Molecular marker and cell death and proliferation analyses provide evidence that ventricular hypoplasia is the result of defective ventricular cell differentiation. Collectively, these data support a hypothesis where physical, functional, and genetic interactions between Nkx2.5 and Mef2c are necessary for ventricle formation.
Vincentz
Joshua W
JW
Riley Heart Research Center, Herman B Wells Center for Pediatric Research Division of Pediatrics Cardiology, Department of Anatomy, Indiana Medical School, Indianapolis, Indiana 46202-5225, USA.
Barnes
Ralston M
RM
Firulli
Beth A
BA
Conway
Simon J
SJ
Firulli
Anthony B
AB
D000818:Animals; D002454:Cell Differentiation; D002460:Cell Line; D018507:Gene Expression Regulation, Developmental; D006321:Heart / Q000196:embryology*; D000072576:Homeobox Protein Nkx-2.5; D018398:Homeodomain Proteins / Q000235:genetics / Q000276:immunology*; D006801:Humans; D064326:MEF2 Transcription Factors; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation / Q000235:genetics; D009206:Myocardium / Q000166:cytology / Q000378:metabolism*; D018006:Myogenic Regulatory Factors / Q000235:genetics / Q000276:immunology*; D011485:Protein Binding; D014157:Transcription Factors / Q000172:deficiency / Q000235:genetics / Q000276:immunology*
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