PUBLICATION
Mechanical Forces Regulate Cardiomyocyte Myofilament Maturation via the VCL-SSH1-CFL Axis
- Authors
- Fukuda, R., Gunawan, F., Ramadass, R., Beisaw, A., Konzer, A., Mullapudi, S.T., Gentile, A., Maischein, H.M., Graumann, J., Stainier, D.Y.R.
- ID
- ZDB-PUB-190910-3
- Date
- 2019
- Source
- Developmental Cell 51(1): 62-77.e5 (Journal)
- Registered Authors
- Maischein, Hans-Martin, Stainier, Didier
- Keywords
- SSH1, cardiac contractility, cardiomyocyte, cofilin, mechanical forces, myofilament maturation, vinculin, zebrafish
- MeSH Terms
-
- Microfilament Proteins/metabolism
- Sodium-Calcium Exchanger/metabolism
- Actins/metabolism
- Phosphoprotein Phosphatases/metabolism*
- Animals
- Actin Cytoskeleton/metabolism
- Heart/embryology*
- Vinculin/metabolism*
- Myofibrils/metabolism
- Zebrafish
- Aminobenzoates/pharmacology
- Gene Expression Regulation, Developmental
- Cofilin 1/metabolism*
- Myocardium/metabolism
- Actin Depolymerizing Factors/metabolism
- Myocytes, Cardiac/metabolism*
- PubMed
- 31495694 Full text @ Dev. Cell
Citation
Fukuda, R., Gunawan, F., Ramadass, R., Beisaw, A., Konzer, A., Mullapudi, S.T., Gentile, A., Maischein, H.M., Graumann, J., Stainier, D.Y.R. (2019) Mechanical Forces Regulate Cardiomyocyte Myofilament Maturation via the VCL-SSH1-CFL Axis. Developmental Cell. 51(1):62-77.e5.
Abstract
Mechanical forces regulate cell behavior and tissue morphogenesis. During cardiac development, mechanical stimuli from the heartbeat are required for cardiomyocyte maturation, but the underlying molecular mechanisms remain unclear. Here, we first show that the forces of the contracting heart regulate the localization and activation of the cytoskeletal protein vinculin (VCL), which we find to be essential for myofilament maturation. To further analyze the role of VCL in this process, we examined its interactome in contracting versus non-contracting cardiomyocytes and, in addition to several known interactors, including actin regulators, identified the slingshot protein phosphatase SSH1. We show how VCL recruits SSH1 and its effector, the actin depolymerizing factor cofilin (CFL), to regulate F-actin rearrangement and promote cardiomyocyte myofilament maturation. Overall, our results reveal that mechanical forces generated by cardiac contractility regulate cardiomyocyte maturation through the VCL-SSH1-CFL axis, providing further insight into how mechanical forces are transmitted intracellularly to regulate myofilament maturation.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping