A novel conditional mouse model for Nkx2-5 reveals transcriptional regulation of cardiac ion channels.

Furtado, Milena B and Wilmanns, Julia C and Chandran, Anjana and Tonta, Mary and Biben, Christine and Eichenlaub, Michael and Coleman, Harold A and Berger, Silke and Bouveret, Romaric and Singh, Reena and Harvey, Richard P and Ramialison, Mirana and Pearson, James T and Parkington, Helena C and Rosenthal, Nadia A and Costa, Mauro W (2016) A novel conditional mouse model for Nkx2-5 reveals transcriptional regulation of cardiac ion channels. Differentiation, 91. pp.29-41. ISSN 1432-0436 (PP OA)

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Link to published document: http://dx.doi.org/10.1016/j.diff.2015.12.003

Abstract

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.

Item Type: Article
Additional Information: Publisher: Elsevier FEB 2016
Keywords: Elsevier
Subjects: R Medicine > R Medicine (General)
Depositing User: Repository Administrator
Date Deposited: 14 Mar 2016 00:18
Last Modified: 15 Jan 2018 00:32
URI: https://eprints.victorchang.edu.au/id/eprint/391

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