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

Mol Cell Biol. 2001 Mar;21(5):1730-6. doi: 10.1128/MCB.21.5.1730-1736.2001.


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 Irx4(Delta ex2/Delta ex2)) was normal during embryogenesis and in early postnatal life. Adult Irx4(Delta ex2/Delta ex2) mice developed a cardiomyopathy characterized by cardiac hypertrophy and impaired contractile function. Prior to the development of cardiomyopathy, Irx4(Delta ex2/Delta ex2) 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 alpha-skeletal actin was markedly increased. Several weeks subsequent to these changes in embryonic and neonatal gene expression, increased expression of hypertrophic markers BNP and beta-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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Actins / biosynthesis
  • Alleles
  • Animals
  • Atrial Natriuretic Factor / biosynthesis
  • Basic Helix-Loop-Helix Transcription Factors
  • Blotting, Northern
  • Cardiomyopathies / genetics*
  • Cardiomyopathies / metabolism
  • Cytokines / biosynthesis
  • DNA, Complementary / metabolism
  • DNA-Binding Proteins / metabolism
  • Down-Regulation
  • Echocardiography
  • Gene Expression Regulation, Developmental*
  • Heterozygote
  • Homeodomain Proteins / biosynthesis
  • Homeodomain Proteins / genetics*
  • Homozygote
  • Mice
  • Mice, Transgenic
  • Models, Genetic
  • Mutagenesis
  • Myocardium / metabolism
  • Reverse Transcriptase Polymerase Chain Reaction
  • Time Factors
  • Transcription Factors / biosynthesis
  • Transcription Factors / metabolism
  • Transgenes
  • Up-Regulation


  • Actins
  • Basic Helix-Loop-Helix Transcription Factors
  • Cytokines
  • DNA, Complementary
  • DNA-Binding Proteins
  • Hand1 protein, mouse
  • Homeodomain Proteins
  • IRX 2
  • Irx1 protein, mouse
  • Irx2 protein, mouse
  • Irx4 protein, mouse
  • Irx5 protein, mouse
  • Transcription Factors
  • helix-loop-helix protein, eHAND
  • Atrial Natriuretic Factor