Journal
DEVELOPMENT
Volume 145, Issue 5, Pages -Publisher
COMPANY BIOLOGISTS LTD
DOI: 10.1242/dev.149823
Keywords
alpha E-catenin; alpha T-catenin; N-cadherin; Cell adhesion; Intercalated disc; Actomyosin; Mechanotransduction; RhoA
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Funding
- National Institutes of Health [HL125988]
- American Heart Association Postdoctoral Fellowship [15POST22700031]
- Bioimaging Core Facility of the Jefferson Kimmel Cancer Center [P30 CA056036]
- [17GRNT33350088]
- NATIONAL CANCER INSTITUTE [P30CA056036] Funding Source: NIH RePORTER
- NATIONAL HEART, LUNG, AND BLOOD INSTITUTE [R56HL125988] Funding Source: NIH RePORTER
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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, alpha E-catenin (Ctnna1) and alpha T-catenin (Ctnna3) genes were deleted to generate cardiac-specific alpha-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 alpha-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.
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