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.
authors.affiliation: Australian Regenerative Medicine Institute, Monash University, Clayton, Vic 3800, Australia; The Jackson Laboratory, ME 04609, United States.
authors.forename: Milena B
authors.initials: MB
authors.lastname: Furtado
authors.affiliation: Australian Regenerative Medicine Institute, Monash University, Clayton, Vic 3800, Australia; Department of Cardiology and Angiology, Hannover Medical School, Hannover, Germany.
authors.forename: Julia C
authors.initials: JC
authors.lastname: Wilmanns
authors.affiliation: Australian Regenerative Medicine Institute, Monash University, Clayton, Vic 3800, Australia.
authors.forename: Anjana
authors.initials: A
authors.lastname: Chandran
authors.affiliation: Department of Physiology, Monash University, Clayton, Vic 3800, Australia.
authors.forename: Mary
authors.initials: M
authors.lastname: Tonta
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Parkville, Vic 3052, Australia; Department of Medical Biology, The University of Melbourne, Parkville, Vic 3052, Australia.
authors.forename: Christine
authors.initials: C
authors.lastname: Biben
authors.affiliation: Australian Regenerative Medicine Institute, Monash University, Clayton, Vic 3800, Australia.
authors.forename: Michael
authors.initials: M
authors.lastname: Eichenlaub
authors.affiliation: Department of Physiology, Monash University, Clayton, Vic 3800, Australia.
authors.forename: Harold A
authors.initials: HA
authors.lastname: Coleman
authors.affiliation: Australian Regenerative Medicine Institute, Monash University, Clayton, Vic 3800, Australia.
authors.forename: Silke
authors.initials: S
authors.lastname: Berger
authors.affiliation: Developmental and Stem Cell Biology Division, Victor Chang Cardiac Research Institute, Darlinghurst, NSW 2010, Australia.
authors.forename: Romaric
authors.initials: R
authors.lastname: Bouveret
authors.affiliation: Developmental and Stem Cell Biology Division, Victor Chang Cardiac Research Institute, Darlinghurst, NSW 2010, Australia.
authors.forename: Reena
authors.initials: R
authors.lastname: Singh
authors.affiliation: Developmental and Stem Cell Biology Division, Victor Chang Cardiac Research Institute, Darlinghurst, NSW 2010, Australia.
authors.forename: Richard P
authors.initials: RP
authors.lastname: Harvey
authors.affiliation: Australian Regenerative Medicine Institute, Monash University, Clayton, Vic 3800, Australia.
authors.forename: Mirana
authors.initials: M
authors.lastname: Ramialison
authors.affiliation: Department of Physiology, Monash University, Clayton, Vic 3800, Australia; Monash Biomedical Imaging, Monash University, Clayton, Vic 3800, Australia.
authors.forename: James T
authors.initials: JT
authors.lastname: Pearson
authors.affiliation: Department of Physiology, Monash University, Clayton, Vic 3800, Australia.
authors.forename: Helena C
authors.initials: HC
authors.lastname: Parkington
authors.affiliation: Australian Regenerative Medicine Institute, Monash University, Clayton, Vic 3800, Australia; National Heart and Lung Institute, Imperial College London, SW3 6LY England, UK; The Jackson Laboratory, ME 04609, United States.
authors.forename: Nadia A
authors.initials: NA
authors.lastname: Rosenthal
authors.affiliation: Australian Regenerative Medicine Institute, Monash University, Clayton, Vic 3800, Australia; The Jackson Laboratory, ME 04609, United States. Electronic address: mauro.dacosta@monash.edu.
authors.forename: Mauro W
authors.initials: MW
authors.lastname: Costa
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D000072237:ERG1 Potassium Channel / Q000235:genetics* / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D006321:Heart / Q000196:embryology / Q000254:growth & development* / Q000503:physiopathology; D006330:Heart Defects, Congenital / Q000235:genetics* / Q000503:physiopathology; D000072576:Homeobox Protein Nkx-2.5 / Q000235:genetics*; D006801:Humans; D007473:Ion Channels / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation
chemical_list: D000072237:ERG1 Potassium Channel; D000072576:Homeobox Protein Nkx-2.5; D007473:Ion Channels; C000606915:Kcnh2 protein, mouse; C484469:Nkx2-5 protein, mouse
keywords: Ion channels; Nkx2-5; Transcriptional regulation