Releasing YAP from an α-catenin trap increases cardiomyocyte proliferation.

A dult mammalian cardiomyocytes possess little endoge-nous proliferative capacity. This innate limitation underlies our inability to reverse heart failure and improve patient outcome after myocardial injury. The mechanisms that restrict adult mammalian cardiomyocyte proliferation have been the intensely scrutinized, and molecular insights are slowly emerging. 1 In this issue of Circulation Research, Li et al 2 add an important new insight by showing that α-catenins, components of cardiomyocyte intercellular junctions, restrain the mitogenic transcriptional coactivator Yes-associated protein (YAP) and thereby inhibit cardiomyocyte proliferation. Intercalated disks mechanically couple cardiomyocytes. Located on the ends of adult mammalian cardiomyocytes, intercalated disks are composed of 2 kinds of adherens junctions , fasciae adherens and desmosomes, interspersed with gap junctions (Figure). In epithelia, such as skin, desmosomes and fasciae adherens constitute physically and molecularly distinct complexes. Epithelial fasciae adherens contain classical cadherins, transmembrane adhesion receptors that mediate cell–cell adhesion through homotypic interactions. The cytoplasmic tails of cadherins interact with catenins (αΕ-catenin [Ctnna1], β-catenin [Ctnnb1], and γ-catenin [Jup, also known as plakoglobin]), which bind the actin cytoskeleton. Analogously, epithelial desmosomes contain desmosomal cadherins (desmoglein and dsmocollin), which interact with γ-catenin (the only protein common to fasciae adherens and desmosomes) and plakophilin. These connect to intermediate filaments through desmoplakin and other plakin family proteins. In heart, the distinction between these 2 types of ad-herens junctions is blurred: mature mammalian intercalated disks contain hybrid junctional complexes containing proteins characteristic of each type of junction, and hence have been referred to as area composita, with local variations yielding regions with more desmosome, or more fascia adherens-like characteristics. 3 Cardiac intercalated disks contain 2 α-catenin isoforms: the widely expressed αE-catenin and the cardiac-restricted αT-catenin (Ctnna3). Interestingly, αT-catenin may contribute to the formation of the hybrid area composita because it interacts with the desmosomal protein plakophilin-2. 4 Cardiac intercellular junctions evolve during heart development , with mature intercalated disks forming only in the postnatal heart. In the fetal heart, desmosomes and fasciae adherens remain more distinct, and both localize widely over the membranes of stellate-shaped cardiomyocytes. As cardio-myocytes mature, they elongate and align their myofibers along the cell's long axis. In the first 2 postnatal weeks, desmosomes and fasciae adherens of murine cardiomyocytes coalesce into area composita that focally cap the cardiomyocyte poles. The essential function of cardiac adherens junctions to join cardiomyocytes mechanically was vividly exposed by genetic inactivation of several intercalated disk components, including γ-, αE-, and αT-catenins. Loss …