Abstract
Shh signaling is required for various cardiac developmental processes including the looping of heart tube and specification of cardiomyogenesis. Consistently, Shh mutant mice display the abnormalities in heart tube formation and specification of the myocardial and outflow tract. A multifunctional receptor Cdo functions as a Shh coreceptor to fully activate Shh signaling and Cdo deficient mice exhibit multiple defects in embryonic development, associated with the decreased Shh activity. However its role in heart development is entirely unknown. This study examined the role of Cdo in heart development and cardiomyogenesis using Cdo deficient (Cdo-/-) mice. Histological and morphological analyses revealed development of dilated cardiomyopathy (DCM) with a frequent death around 3 weeks of age. Echocardiographic analyses of Cdo-/- mice at 2 weeks confirmed the dilated phenotype of the heart with a significant decrease in the left ventricular fractional shortening. Patch clamp experiments revealed an increase in Ito and reduction in IK1, without any significant changes in action potential duration (APD) in Cdo-/- cariomyocytes. A major gap junctional protein Connexin 43 (Cx43) appears to be localized at the lateral border of the Cdo-/- cardiomyocytes whereas Cx43 remained predominately at the intercalated disk in wildtype cardiomyocytes. Furthermore the phosphorylation status of Cx43 was altered in Cdo-/- hearts. Taken together, these data suggest that Cdo signaling may influence the phosphorylation status and distribution of Cx43 thereby regulating intercellular communication and functionality of cardiomyocytes.
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