Nkx2-5 pathways and congenital heart disease: Loss of ventricular myocyte lineage specification leads to progressive cardiomyopathy and complete heart block

Mohammad Pashmforoush, Jonathan T. Lu, Hanying Chen, Tara St. Amand, Richard Kondo, Sylvain Pradervand, Sylvia M. Evans, Bob Clark, James R. Feramisco, Wayne Giles, Siew Yen Ho, D. Woodrow Benson, Gary (Michael) Silberbach, Weinian Shou, Kenneth R. Chien

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309 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)373-386
Number of pages14
JournalCell
Volume117
Issue number3
DOIs
StatePublished - Apr 30 2004
Externally publishedYes

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ASJC Scopus subject areas

  • Cell Biology
  • Molecular Biology

Cite this

Pashmforoush, M., Lu, J. T., Chen, H., St. Amand, T., Kondo, R., Pradervand, S., Evans, S. M., Clark, B., Feramisco, J. R., Giles, W., Ho, S. Y., Benson, D. W., Silberbach, G. M., Shou, W., & Chien, K. R. (2004). Nkx2-5 pathways and congenital heart disease: Loss of ventricular myocyte lineage specification leads to progressive cardiomyopathy and complete heart block. Cell, 117(3), 373-386. https://doi.org/10.1016/S0092-8674(04)00405-2