10 Circulation Research January 2, 2015 αT-catenin driven by Myh6-Cre. 2 These double knockout (DKO) mice survived to postnatal life. At 6 weeks, the hearts were normal in size, but cardiomyocyte number was higher and cardiomyocyte size was lower than controls. Increased cardiomyocyte number was linked to greater cell cycle activity. Previously, αE-catenin was shown to mediate contact inhibition of keratinocyte proliferation via sequestration of YAP at adherens junctions. 13 Therefore, Li et al2 investigated YAP activity in the αE/αT DKO hearts and found increased nuclear YAP. Enhanced YAP activity was essential for the proproliferative effect of α-catenin loss of function because increased cell cycle activity observed in cultured neonatal cardiomyocytes with siRNA-mediated αE/αT knockdown was blunted by simultaneous YAP knockdown. Interestingly, the mechanism of YAP activation seems to differ from what was previously reported for αE-catenin regulation of YAP in keratinocytes, where αE-catenin inhibited YAP dephosphorylation by the phosphatase PP2Ac. 13 In contrast, in DKO hearts, both phospho-and total YAP levels were increased, leading to more activated YAP but only a slight reduction of the phospho: total YAP ratio. 2 Additional studies are needed to define the mechanistic link between αE/αT-catenin ablation in DKO hearts and YAP activation.

Li et al2 also examined the effect of αE/αT-catenin ablation in adult cardiomyocytes driven by Myh6-MerCreMer. Although fetal inactivation of either αE-or αT-catenin caused adult onset cardiomyopathy, 8, 9 interestingly, adult stage inactivation of both αE/αT-catenin (IN-DKO) was compatible with survival for> 1 year and did not cause histological abnormalities. Cardiomyocyte proliferation was not elevated in unstressed hearts. However, MI of IN-DKO mice showed that the inactivation of αE/αT-catenins had a surprising protective effect: IN-DKO mice had better cardiac function and reduced cardiac remodeling at 9 and 12 weeks post MI. These changes were associated with increased cardiomyocyte cell cycle activity in the border and ischemic zones, and with an increased fraction of cardiomyocytes with YAP nuclear localization.