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

To define the role of Irx4, a member of the Iroquois family of homeobox tra nscription factors in mammalian heart development and function, we disrupte d the murine Irx4 gene. Cardiac morphology in Irx4-deficient mice (designat ed Irx4(Delta ex2/Delta ex2)) was normal during embryogenesis and in early postnatal life. Adult Irx4(Delta ex2/Delta ex2) mice developed a cardiomyop athy characterized by cardiac hypertrophy and impaired contractile function . Prior to the development of cardiomyopathy, Irx4(Delta ex2/Delta ex2) hea rts had abnormal ventricular gene expression: Irx4-deficient embryos exhibi ted reduced ventricular expression of the basic helix-loop-helix transcript ion factor eHand (Hand1), increased Irx2 expression, and ventricular induct ion of an atrial chamber-specific transgene. In neonatal hearts, ventricula r expression of atrial natriuretic factor and alpha -skeletal actin was mar kedly 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 los s of Irx4 function. We conclude that Irx4 is not sufficient for ventricular chamber formation but is required far the establishment of some components of a ventricle-specific gene expression program. In the absence of genes u nder the control of Irx4, ventricular function deteriorates and cardiomyopa thy ensues.