title: Nkx2-5 pathways and congenital heart disease; loss of ventricular myocyte lineage specification leads to progressive cardiomyopathy and complete heart block.
abstract: 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.
authors.affiliation: UCSD Institute of Molecular Medicine, University of California San Diego School of Medicine, La Jolla, CA 92093, USA.
authors.forename: Mohammad
authors.initials: M
authors.lastname: Pashmforoush
authors.forename: Jonathan T
authors.initials: JT
authors.lastname: Lu
authors.forename: Hanying
authors.initials: H
authors.lastname: Chen
authors.forename: Tara St
authors.initials: TS
authors.lastname: Amand
authors.forename: Richard
authors.initials: R
authors.lastname: Kondo
authors.forename: Sylvain
authors.initials: S
authors.lastname: Pradervand
authors.forename: Sylvia M
authors.initials: SM
authors.lastname: Evans
authors.forename: Bob
authors.initials: B
authors.lastname: Clark
authors.forename: James R
authors.initials: JR
authors.lastname: Feramisco
authors.forename: Wayne
authors.initials: W
authors.lastname: Giles
authors.forename: Siew Yen
authors.initials: SY
authors.lastname: Ho
authors.forename: D Woodrow
authors.initials: DW
authors.lastname: Benson
authors.forename: Michael
authors.initials: M
authors.lastname: Silberbach
authors.forename: Weinian
authors.initials: W
authors.lastname: Shou
authors.forename: Kenneth R
authors.initials: KR
authors.lastname: Chien
mesh_terms: 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
chemical_list: D000072576:Homeobox Protein Nkx-2.5; D018398:Homeodomain Proteins; C484469:Nkx2-5 protein, mouse; D014157:Transcription Factors; D000110:Acetylcholinesterase