Cdon deficiency causes cardiac remodeling through hyperactivation of WNT/β-catenin signaling

Upon injury, reactivated Wnt/β-catenin signaling is implicated in cardiac remodeling and cardiomyopathy, thus it is an attractive target for intervention of cardiac diseases. Here, we demonstrate a role of a cell surface receptor Cdon in preventing cardiac remodeling through suppression of Wnt signaling. Cdon^-/- mice develop cardiac dysfunction and fibrosis with altered expression of remodeling genes. Cdon deficiency causes aberrant localization and function of gap junction protein connexin 43, correlating with hyperactivated Wnt signaling. Blocking of Wnt signaling in Cdon-depleted cardiomyocytes attenuates aberrant intercellular coupling. Conversely, Wnt activator causes aberrant activation of gap junction with decreased Cdon levels, suggestive of a feedback mechanism. These data suggest that Cdon is required for the control of Wnt signaling to prevent cardiac remodeling.