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Molecular and Cellular Biology, March 2001, p. 1730-1736, Vol. 21, No. 5
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.5.1730-1736.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Cardiomyopathy in Irx4-Deficient Mice Is Preceded by Abnormal Ventricular Gene Expression

Benoit G. Bruneau,1,dagger Zheng-Zheng Bao,1 Diane Fatkin,2 Jose Xavier-Neto,3,4 Dimitrios Georgakopoulos,5 Colin T. Maguire,6 Charles I. Berul,6 David A. Kass,5 Mercedes L. Kuroski-de Bold,7 Adolfo J. de Bold,7 David A. Conner,1,8 Nadia Rosenthal,3 Constance L. Cepko,1,8 Christine E. Seidman,1,2,9 and J. G. Seidman1,8,*

Department of Genetics1 and Howard Hughes Medical Institute,8 Harvard Medical School, Cardiovascular Division, Department of Medicine,2 and Howard Hughes Medical Institute,9 Brigham and Women's Hospital, and Children's Hospital and Harvard Medical School,6 Boston, and Cardiovascular Research Center, Massachusetts General Hospital, Charlestown,3 Massachusetts; Laboratório de Genética e Cardiologia Molecular, Instituto do Coração (InCor) HC-FMUSP, São Paulo 05403-000, Brazil4; Johns Hopkins University, Baltimore, Maryland5; and University of Ottawa Heart Institute at the Ottawa Hospital, Ottawa, Ontario K1Y 4H9, Canada7

Received 28 September 2000/Returned for modification 10 November 2000/Accepted 28 November 2000

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 Irx4Delta ex2/Delta ex2) was normal during embryogenesis and in early postnatal life. Adult Irx4Delta ex2/Delta ex2 mice developed a cardiomyopathy characterized by cardiac hypertrophy and impaired contractile function. Prior to the development of cardiomyopathy, Irx4Delta 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.

* Corresponding author. Mailing address: Department of Genetics, Harvard Medical School, 200 Longwood Ave., Boston, MA 02115. Phone: (617) 432-7830. Fax: (617) 432-7832. E-mail: seidman{at}rascal.med.harvard.edu.

dagger Present address: Division of Cardiovascular Research, The Hospital for Sick Children, Toronto, Ontario, Canada.

Molecular and Cellular Biology, March 2001, p. 1730-1736, Vol. 21, No. 5
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.5.1730-1736.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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