@ Institute of Molecular Biology and Genetics, Ukraine
Adhesion proteins more than just cardiomyocytes coupling
The structural integrity of the heart is necessary for its function and is maintained by the intercalated discs (IDs) that comprise the end-to-end connections between myocytes. IDs consist of three main junctional complexes: adherens junctions (AJs), gap junctions and desmosomes. Each of these junctional complexes is extremely important for maintenance of normal mechanical and electrical coupling between cardiomyocytes, and therefore for normal heart function. In the heart, the AJs are comprised predominantly of N-cadherin, which is highly expressed in the developing and mature myocardium. Classical cadherins are transmembrane proteins that mediate specific cell–cell adhesion. At the cytoplasmic side of the junction, either b-catenin or plakoglobin can interact directly with a core region within the C-terminus of the cadherin cytoplasmic domain. The N-terminal ortion of b-catenin or plakoglobin interacts with a-catenin, which links this complex to the cytoskeleton.
Wide known that intercellular adhesion is important for the development of any multicellular organism, but here we would like discuss other function of adherens junctions proteins in embryonic and adult heart. In our work we have focused on signalling function of b- and a-E – catenin. Beta –catenin is main transcriptional co-activator of canonical Wnt –signalling and in such way it involved in cells differentiation and proliferation control. Signalling function of a-E catenin recovered during last decades, it was shown that last one can regulate a few important signalling passway including canonical Wnt, Hippo, Hedgehog and NF-κB. Thus signalling function of b-catenin in heart is controversial and signalling function of a-E catenin is fur from understood.
With conditional knockout mice using we have focused on signalling function of a E-catenin an b-catenin function in heart development and maturation. We observed the adult heart maturation delay in mice with b-catenin haploinsufficiency. Moreover, we registered fetal genes up-regulation in mutant mice together with canonical Wnt down-regulation. Our data suggest that canonical Wnt and b-catenin is highly important for new born heart maturation and terminal differentiation of cardiomyocytes. We also recovered that even basal level of canonical Wnt activity is critically important for adult heart adaptation for stress. This data supported by other experiments where we registered heart enlarged hypertrophy and heart failure in mice with a-E catenin missing. In these mice we registered higher level of b-catenin and Yap dependent transcription.