Dysregulation of connexins and inactivation of NFATc1 in the cardiovascular system of Nkx2-5 null mutants.
In humans, mutations of the gene encoding the transcription factor Nkx2-5 result in the heart in electrical conduction defects and morphological abnormalities. In this organ Nkx2-5 is expressed in both the myocardium and the endocardium. Connexins (Cxs) are gap junction channel proteins that have been shown to be involved in both heart development and cardiac electrical conduction, suggesting a possible correlation between expression of Cxs and Nkx2-5. To evaluate this correlation, the expression of Cxs has been investigated in the cardiovascular system of wild-type and Nkx2-5-/- 9.2 days post-conception (dpc) mouse embryos. The disruption of the Nkx2-5 gene results in the loss of Cx43 in the heart, due in part to the poor development of the ventricular trabecular network, as well as specific downregulation of Cx45 gene expression. In addition, the nuclear translocation of NFATc1 in the endocardial endothelial cells is inhibited in the Nkx2-5-/- embryos. These results indicate for the first time that Nkx2-5 is involved in the transcriptional regulation of the Cx45 gene expression. In the mutant embryos the aorta is collapsed, and the vascular endothelial Cxs, Cx40 and Cx37, are no longer expressed in its posterior region. Poor development of the trabeculae and downregulation of Cx45 may contribute both to failure of the myocardial function and to hemodynamic insufficiency. The latter, in turn, may result in the dysregulation of Cx40 and -37 expressions along the whole length of the aorta. Direct or indirect effects of Nkx2-5 inactivation on the Cx45 gene expression could explain the absence of the endocardial cushions in the heart of Nkx2-5-/- embryos.
Dupays
Laurent
L
Laboratoire de Génétique et Physiologie du Développement (UMR CNRS 6545), Institut de Biologie du Développement de Marseille, Université de la Méditerranée, 13288 Marseille cedex 9, France.
Jarry-Guichard
Thérèse
T
Mazurais
David
D
Calmels
Thierry
T
Izumo
Seigo
S
Gros
Daniel
D
Théveniau-Ruissy
Magali
M
D000818:Animals; D001483:Base Sequence; D018376:Cardiovascular Abnormalities / Q000196:embryology / Q000235:genetics / Q000503:physiopathology; D002319:Cardiovascular System / Q000196:embryology / Q000378:metabolism*; D018031:Connexin 43 / Q000235:genetics / Q000378:metabolism; D017630:Connexins / Q000235:genetics* / Q000378:metabolism; D004247:DNA / Q000235:genetics; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D000072576:Homeobox Protein Nkx-2.5; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D009200:Myocardial Contraction / Q000235:genetics / Q000502:physiology; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000037:antagonists & inhibitors* / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D000097003:Gap Junction alpha-5 Protein; D000097006:Gap Junction alpha-4 Protein
D018031:Connexin 43; D017630:Connexins; D004247:DNA; D004268:DNA-Binding Proteins; D000072576:Homeobox Protein Nkx-2.5; D018398:Homeodomain Proteins; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins; D012333:RNA, Messenger; D014157:Transcription Factors; D000097003:Gap Junction alpha-5 Protein; D000097006:Gap Junction alpha-4 Protein; C494003:NFATC1 protein, human; C494005:Nfatc1 protein, mouse; C484469:Nkx2-5 protein, mouse; C082920:connexin 45