Nkx2-5 pathways and congenital heart disease; loss of ventricular myocyte lineage specification leads to progressive cardiomyopathy and complete heart block.
Human mutations in Nkx2-5 lead to progressive cardiomyopathy and conduction defects via unknown mechanisms. To define these pathways, we generated mice with a ventricular-restricted knockout of Nkx2-5, which display no structural defects but have progressive complete heart block, and massive trabecular muscle overgrowth found in some patients with Nkx2-5 mutations. At birth, mutant mice display a hypoplastic atrioventricular (AV) node and then develop selective dropout of these conduction cells. Transcriptional profiling uncovered the aberrant expression of a unique panel of atrial and conduction system-restricted target genes, as well as the ectopic, high level BMP-10 expression in the adult ventricular myocardium. Further, BMP-10 is shown to be necessary and sufficient for a major component of the ventricular muscle defects. Accordingly, loss of ventricular muscle cell lineage specification into trabecular and conduction system myocytes is a new mechanistic pathway for progressive cardiomyopathy and conduction defects in congenital heart disease.
Pashmforoush
Mohammad
M
UCSD Institute of Molecular Medicine, University of California San Diego School of Medicine, La Jolla, CA 92093, USA.
Lu
Jonathan T
JT
Chen
Hanying
H
Amand
Tara St
TS
Kondo
Richard
R
Pradervand
Sylvain
S
Evans
Sylvia M
SM
Clark
Bob
B
Feramisco
James R
JR
Giles
Wayne
W
Ho
Siew Yen
SY
Benson
D Woodrow
DW
Silberbach
Michael
M
Shou
Weinian
W
Chien
Kenneth R
KR
D000110:Acetylcholinesterase / Q000378:metabolism; D000375:Aging; D000818:Animals; D000831:Animals, Newborn; D009202:Cardiomyopathies / Q000235:genetics* / Q000473:pathology; D019070:Cell Lineage; D004553:Electric Conductivity; D004562:Electrocardiography; D017353:Gene Deletion; D015870:Gene Expression; D020869:Gene Expression Profiling; D018390:Gene Targeting; D017930:Genes, Reporter; D006327:Heart Block / Q000196:embryology / Q000235:genetics* / Q000503:physiopathology; D006330:Heart Defects, Congenital / Q000150:complications / Q000503:physiopathology*; D006352:Heart Ventricles / Q000166:cytology; D000072576:Homeobox Protein Nkx-2.5; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D032383:Myocytes, Cardiac / Q000166:cytology; D015203:Reproducibility of Results; D013997:Time Factors; D014157:Transcription Factors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic
D000072576:Homeobox Protein Nkx-2.5; D018398:Homeodomain Proteins; C484469:Nkx2-5 protein, mouse; D014157:Transcription Factors; D000110:Acetylcholinesterase