Cardiomyopathy in Irx4-deficient mice is preceded by abnormal ventricular gene expression

B. G. Bruneau, Z. Z. Bao, D. Fatkin, J. Xavier-Neto, D. Georgakopoulos, C. T. Maguire, C. I. Berul, D. A. Kass, M. L. Kuroski-De Bold, A. J. De Bold, D. A. Conner, N. Rosenthal, C. L. Cepko, C. E. Seidman, J. G. Seidman

Research output: Contribution to journalArticle

Abstract

To define the role of Irx4, a member of the Iroquois family of homeobox transcription factors in mammalian heart development and function, we disrupted the murine Irx4 gene. Cardiac morphology in Irx4-deficient mice (designated Irx4Δex2/Δex2) was normal during embryogenesis and in early postnatal life. Adult Irx4Δex2/Δex2 mice developed a cardiomyopathy characterized by cardiac hypertrophy and impaired contractile function. Prior to the development of cardiomyopathy, Irx4Δex2/Δex2 hearts had abnormal ventricular gene expression: Irx4-deficient embryos exhibited reduced ventricular expression of the basic helix-loop-helix transcription factor eHand (Hand1), increased Irx2 expression, and ventricular induction of an atrial chamber-specific transgene. In neonatal hearts, ventricular expression of atrial natriuretic factor and α-skeletal actin was markedly increased. Several weeks subsequent to these changes in embryonic and neonatal gene expression, increased expression of hypertrophic markers BNP and [β-myosin heavy chain accompanied adult-onset cardiac hypertrophy. Cardiac expression of Irx1, Irx2, and Irx5 may partially compensate for loss of Irx4 function. We conclude that Irx4 is not sufficient for ventricular chamber formation but is required for the establishment of some components of a ventricle-specific gene expression program. In the absence of genes under the control of Irx4, ventricular function deteriorates and cardiomyopathy ensues.

Original languageEnglish (US)
Pages (from-to)1730-1736
Number of pages7
JournalMolecular and cellular biology
Volume21
Issue number5
DOIs
StatePublished - Feb 26 2001

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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    Bruneau, B. G., Bao, Z. Z., Fatkin, D., Xavier-Neto, J., Georgakopoulos, D., Maguire, C. T., Berul, C. I., Kass, D. A., Kuroski-De Bold, M. L., De Bold, A. J., Conner, D. A., Rosenthal, N., Cepko, C. L., Seidman, C. E., & Seidman, J. G. (2001). Cardiomyopathy in Irx4-deficient mice is preceded by abnormal ventricular gene expression. Molecular and cellular biology, 21(5), 1730-1736. https://doi.org/10.1128/MCB.21.5.1730-1736.2001