Open AccessAlpha-catenin-dependent cytoskeletal tension controls Yap activity in the heart
Author(s) -
Alexia Vite,
Caimei Zhang,
Roslyn Yi,
Sabrina Emms,
Glenn L. Radice
Publication year - 2018
Publication title -
development
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.754
H-Index - 325
eISSN - 1477-9129
pISSN - 0950-1991
DOI - 10.1242/dev.149823
Subject(s) - rhoa , catenin , biology , microbiology and biotechnology , intercalated disc , cadherin , myosin , beta catenin , cell growth , cytoskeleton , contractility , myocyte , cell adhesion , vinculin , cell , signal transduction , focal adhesion , endocrinology , wnt signaling pathway , biochemistry , gap junction , intracellular
Shortly after birth, muscle cells of the mammalian heart lose their ability to divide. At the same time, the N-cadherin/catenin cell adhesion complex accumulates at the cell termini creating a specialized type of cell-cell contact called the intercalated disc (ICD). To investigate the relationship between ICD maturation and proliferation, αE-catenin (Ctnna1) and αT-catenin (Ctnna3) genes were deleted to generate cardiac-specific α-catenin double knockout (DKO) mice. DKO mice exhibited aberrant N-cadherin expression, mislocalized actomyosin activity, and increased cardiomyocyte proliferation that was dependent on Yap activity. To assess effects on tension, cardiomyocytes were cultured on deformable polyacrylamide hydrogels of varying stiffness. When grown on stiff substrate, DKO cardiomyocytes exhibited increased cell spreading, nuclear Yap, and proliferation. A low dose of either a myosin or RhoA inhibitor was sufficient to block Yap accumulation in the nucleus. Finally, activation of RhoA was sufficient to increase nuclear Yap in wild-type cardiomyocytes. These data demonstrate that α-catenins regulate ICD maturation and actomyosin contractility, which, in turn, controls Yap subcellular localization, thus providing an explanation for the loss of proliferative capacity in the newborn mammalian heart.