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

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.
Original languageEnglish
Pages (from-to)29 - 41
Number of pages13
JournalDifferentiation
Volume91
Issue number1-3
DOIs
Publication statusPublished - 2016

Cite this

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title = "A novel conditional mouse model for Nkx2-5 reveals transcriptional regulation of cardiac ion channels",
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.",
author = "Furtado, {Milena B} and Julia Wilmanns and Anjana Chandran and Tonta, {Mary A} and Christine Biben and Eichenlaub, {Michael Peter} and Coleman, {Harold A} and Silke Berger and Romaric Bouveret and Reena Singh and Harvey, {Richard P} and Ramialison, {Mirana Soa Manarivo} and Pearson, {James T} and Parkington, {Helena C} and Rosenthal, {Nadia A} and {Da Costa}, {Mauro W}",
year = "2016",
doi = "10.1016/j.diff.2015.12.003",
language = "English",
volume = "91",
pages = "29 -- 41",
journal = "Differentiation",
issn = "0301-4681",
publisher = "Elsevier",
number = "1-3",

}

A novel conditional mouse model for Nkx2-5 reveals transcriptional regulation of cardiac ion channels. / Furtado, Milena B; Wilmanns, Julia; Chandran, Anjana; Tonta, Mary A; Biben, Christine; Eichenlaub, Michael Peter; Coleman, Harold A; Berger, Silke; Bouveret, Romaric; Singh, Reena; Harvey, Richard P; Ramialison, Mirana Soa Manarivo; Pearson, James T; Parkington, Helena C; Rosenthal, Nadia A; Da Costa, Mauro W.

In: Differentiation, Vol. 91, No. 1-3, 2016, p. 29 - 41.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - A novel conditional mouse model for Nkx2-5 reveals transcriptional regulation of cardiac ion channels

AU - Furtado, Milena B

AU - Wilmanns, Julia

AU - Chandran, Anjana

AU - Tonta, Mary A

AU - Biben, Christine

AU - Eichenlaub, Michael Peter

AU - Coleman, Harold A

AU - Berger, Silke

AU - Bouveret, Romaric

AU - Singh, Reena

AU - Harvey, Richard P

AU - Ramialison, Mirana Soa Manarivo

AU - Pearson, James T

AU - Parkington, Helena C

AU - Rosenthal, Nadia A

AU - Da Costa, Mauro W

PY - 2016

Y1 - 2016

N2 - 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.

AB - 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.

U2 - 10.1016/j.diff.2015.12.003

DO - 10.1016/j.diff.2015.12.003

M3 - Article

VL - 91

SP - 29

EP - 41

JO - Differentiation

JF - Differentiation

SN - 0301-4681

IS - 1-3

ER -