PUBLICATION
Yap is Required for Scar Formation but not Myocyte Proliferation During Heart Regeneration in Zebrafish
- Authors
- Flinn, M.A., Jeffery, B.E., O'Meara, C.C., Link, B.A.
- ID
- ZDB-PUB-181009-5
- Date
- 2018
- Source
- Cardiovascular research 115(3): 570-577 (Journal)
- Registered Authors
- Link, Brian
- Keywords
- none
- Datasets
- GEO:GSE112452
- MeSH Terms
-
- Animals
- Animals, Genetically Modified
- Apoptosis Regulatory Proteins/genetics
- Apoptosis Regulatory Proteins/metabolism
- Cell Proliferation*
- Cells, Cultured
- Cicatrix/genetics
- Cicatrix/metabolism*
- Cicatrix/pathology
- Cicatrix/physiopathology
- Cold Temperature
- Disease Models, Animal
- Fibroblasts/metabolism
- Fibroblasts/pathology
- Fibrosis
- Gene Expression Regulation
- Heart Injuries/genetics
- Heart Injuries/metabolism*
- Heart Injuries/pathology
- Heart Injuries/physiopathology
- Macrophages/metabolism
- Macrophages/pathology
- Myocytes, Cardiac/metabolism*
- Myocytes, Cardiac/pathology
- Rats
- Regeneration*
- Signal Transduction
- Trans-Activators/genetics
- Trans-Activators/metabolism*
- Ventricular Remodeling
- Zebrafish/genetics
- Zebrafish/metabolism
- Zebrafish Proteins/genetics
- Zebrafish Proteins/metabolism*
- PubMed
- 30295714 Full text @ Cardiovasc. Res.
Citation
Flinn, M.A., Jeffery, B.E., O'Meara, C.C., Link, B.A. (2018) Yap is Required for Scar Formation but not Myocyte Proliferation During Heart Regeneration in Zebrafish. Cardiovascular research. 115(3):570-577.
Abstract
Aims The Hippo signaling pathway regulates multiple cellular processes during organ development and maintenance by modulating activity of the transcriptional cofactor Yap. Core components of this pathway are required for neonatal mouse heart regeneration, however, investigations to date have typically focused on expression and activity in cardiomyocytes. Due to the regenerative capacity of zebrafish and the fact that global loss of Yap is not fully embryonic lethal in zebrafish, we leveraged a yap null mutant to investigate the impact of constitutive Yap deletion during zebrafish heart regeneration.
Methods and results Following cryoinjury in adult hearts, myocyte proliferation was not decreased in yap mutants, contrary to expectations based on mouse data. Experiments in larval zebrafish (Danio rerio) revealed that deletion of either Yap or Taz had a modest effect on heart growth, reducing gross organ size, while their combined deletion was synergistic; thus, Yap and Taz share some overlapping roles in zebrafish heart development. Surprisingly, adult yap mutants exhibited decreased collagen composition at 7 days post injury, suggesting a critical role for Yap in scar formation during heart regeneration. siRNA-mediated Yap knockdown in primary rat (Rattus norvegicus) cardiac cells revealed a fibroblast-specific role for Yap in controlling the expression of cytoskeletal and myofibroblast activation genes, as well as pro-inflammatory cyto/chemokines. Corroborating these RNAseq data, we observed increased macrophage infiltration in the scars of yap mutants at 7 days post injury.
Conclusions These results suggest that Yap deletion has minimal effect on myocyte proliferation in adults, but significantly influences scar formation and immune cell infiltration during zebrafish heart regeneration. Collectively, these data suggest an unexpected role for Yap in matrix formation and macrophage recruitment during heart regeneration.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping