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

Milena B Furtado, Julia Wilmanns, Anjana Chandran, Mary A Tonta, Christine Biben, Michael Peter Eichenlaub, Harold A Coleman, Silke Berger, Romaric Bouveret, Reena Singh, Richard P Harvey, Mirana Soa Manarivo Ramialison, James T Pearson, Helena C Parkington, Nadia A Rosenthal, Mauro W Da Costa

Research output: Contribution to journalArticleResearchpeer-review

18 Citations (Scopus)


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.
Original languageEnglish
Pages (from-to)29 - 41
Number of pages13
Issue number1-3
Publication statusPublished - 2016

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