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To define the role of Irx4, a member of the Iroquoisfamily of homeobox transcription factors in mammalian heart development and function, we disrupted the murine Irx4 gene. Cardiac morphology in Irx4-deficient mice (designatedIrx4^Δex2/Δex2) was normal during embryogenesis and in early postnatal life. AdultIrx4^Δex2/Δex2 mice developed a cardiomyopathy characterized by cardiac hypertrophy and impaired contractile function. Prior to the development of cardiomyopathy, Irx4^Δex2/Δex2 hearts had abnormal ventricular gene expression: Irx4-deficient embryos exhibited reduced ventricular expression of the basic helix-loop-helix transcription factor eHand (Hand1), increasedIrx2 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 …