A novel conditional mouse model for Nkx2-5 reveals transcriptional regulation of cardiac ion channels
- Furtado, MB; Wilmanns, JC; Chandran, A; Tonta, M; Biben, C; Eichenlaub, M; Coleman, HA; Berger, S; Bouveret, R; Singh, R; Harvey, RP; Ramialison, M; Pearson, JT; Parkington, HC; Rosenthal, NA; Costa, MW;
Publication Year 2016-03, Volume 91, Issue #1-3, Page 29-41
- Journal Title
- Publication Type
- Journal Article
- Nkx2-5 is one of the master regulators of cardiac development, homeostasis and disease. This transcription factor has been previously associated with a suite of cardiac congenital malformations and impairment of electrical activity. When disease causative mutations in transcription factors are considered, NKX2-5 gene dysfunction is the most common abnormality found in patients. Here we describe a novel mouse model and subsequent implications of Nkx2-5 loss for aspects of myocardial electrical activity. In this work we have engineered a new Nkx2-5 conditional knockout mouse in which flox sites flank the entire Nkx2-5 locus, and validated this line for the study of heart development, differentiation and disease using a full deletion strategy. While our homozygous knockout mice show typical embryonic malformations previously described for the lack of the Nkx2-5 gene, hearts of heterozygous adult mice show moderate morphological and functional abnormalities that are sufficient to sustain blood supply demands under homeostatic conditions. This study further reveals intriguing aspects of Nkx2-5 function in the control of cardiac electrical activity. Using a combination of mouse genetics, biochemistry, molecular and cell biology, we demonstrate that Nkx2-5 regulates the gene encoding Kcnh2 channel and others, shedding light on potential mechanisms generating electrical abnormalities observed in patients bearing NKX2-5 dysfunction and opening opportunities to the study of novel therapeutic targets for anti-arrhythmogenic therapies.
- WEHI Research Division(s)
- Molecular Medicine
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- Publisher's Version
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Creation Date: 2016-03-15 03:47:43Last Modified: 2016-05-09 12:38:55