期刊
DIFFERENTIATION
卷 91, 期 1-3, 页码 29-41出版社
ELSEVIER SCI LTD
DOI: 10.1016/j.diff.2015.12.003
关键词
Nkx2-5; Transcriptional regulation; Ion channels
资金
- State Government of Victoria
- Australian Government
- NHMRC-Australia Fellowship
- NHMRC Project Grant [1069710, 1042478]
- ARC Stem Cells Australia
- NHMRC/NHF Career Development Fellowship [1049980]
- ARC Discovery Project [DP140101067]
- National Health and Medical Research Council of Australia [1069710] Funding Source: NHMRC
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. (C) 2016 International Society of Differentiation. Published by Elsevier B.V. All rights reserved.
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