α-Catenin-dependent cytoskeletal tension controls Yap activity in the heart

Development. 2018 Mar 8;145(5):dev149823. doi: 10.1242/dev.149823.

Abstract

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 a 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, control Yap subcellular localization, thus providing an explanation for the loss of proliferative capacity in the newborn mammalian heart.

Keywords: Actomyosin; Cell adhesion; Intercalated disc; Mechanotransduction; N-cadherin; RhoA; αE-catenin; αT-catenin.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / metabolism*
  • Adaptor Proteins, Signal Transducing / physiology
  • Animals
  • Animals, Newborn
  • Cell Communication / genetics
  • Cell Cycle Proteins
  • Cells, Cultured
  • Cytoskeleton / metabolism*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Myocardium / metabolism*
  • Myocytes, Cardiac / metabolism*
  • Myocytes, Cardiac / physiology
  • Phosphoproteins / metabolism*
  • Phosphoproteins / physiology
  • YAP-Signaling Proteins
  • alpha Catenin / genetics
  • alpha Catenin / physiology*

Substances

  • Adaptor Proteins, Signal Transducing
  • CTNNA3 protein, mouse
  • Cell Cycle Proteins
  • Ctnna1 protein, mouse
  • Phosphoproteins
  • YAP-Signaling Proteins
  • Yap1 protein, mouse
  • alpha Catenin