Absence of Msx2 does not affect cardiac conduction or rescue conduction defects associated with Nkx2-5 mutation.
BACKGROUND
The transcription factors governing embryonic development of the AV conduction system are largely unknown. Heterozygous mutations of the cardiac transcription factor Nkx2-5 cause AV conduction defects, which are associated with anatomic hypoplasia of the conduction system. In situ expression patterns of Msx2 in the mouse and chick embryonic heart have suggested a developmental function for this transcription factor. Homozygous Nkx2-5 knockout mouse embryos express Msx2 ectopically throughout the myocardium, suggesting Msx2 affects conduction system development through a transcriptional cascade starting with Nkx2-5. Several observations support a model in which Msx2 negatively regulates formation of the conduction system and inappropriate Msx2 up-regulation causes the conduction defects associated with Nkx2-5 mutation.


RESULTS
We obtained surface ECGs and performed intracardiac electrophysiologic studies in Msx2 knockout mice and in Nkx2-5 wild-type and heterozygous null mutant mice in an Msx2 null mutant background. Msx2 null mutant mice had normal cardiac conduction and no increased vulnerability to inducible arrhythmia. Absence of Msx2 did not alter the conduction defects observed in heterozygous Nkx2-5 knockout mice.


CONCLUSIONS
Msx2 likely does not contribute to development of the conduction system. Abnormal Msx2 expression likely does not cause the AV conduction defects present in Nkx2-5 knockout mice.
Jay
Patrick Y
PY
Department of Cardiology, Children's Hospital, Boston, Massachusetts 02139, USA. jay_p@kids.wustl.edu
Maguire
Colin T
CT
Wakimoto
Hiroko
H
Izumo
Seigo
S
Berul
Charles I
CI
D000818:Animals; D001146:Arrhythmia, Sinus / Q000503:physiopathology*; D001283:Atrioventricular Node / Q000503:physiopathology*; D004268:DNA-Binding Proteins / Q000172:deficiency* / Q000235:genetics; D004562:Electrocardiography; D020022:Genetic Predisposition to Disease / Q000235:genetics; D006329:Heart Conduction System / Q000503:physiopathology*; D000072576:Homeobox Protein Nkx-2.5; D018398:Homeodomain Proteins / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D014157:Transcription Factors / Q000172:deficiency* / Q000235:genetics
D004268:DNA-Binding Proteins; D000072576:Homeobox Protein Nkx-2.5; D018398:Homeodomain Proteins; C084119:MSX2 protein; C484469:Nkx2-5 protein, mouse; D014157:Transcription Factors