PUBLICATION

Proteolysis regulates cardiomyocyte maturation and tissue integration

Authors
Fukuda, R., Gunawan, F., Beisaw, A., Jimenez-Amilburu, V., Maischein, H.M., Kostin, S., Kawakami, K., Stainier, D.Y.
ID
ZDB-PUB-170218-5
Date
2017
Source
Nature communications   8: 14495 (Journal)
Registered Authors
Kawakami, Koichi, Maischein, Hans-Martin, Stainier, Didier
Keywords
Cell biology, Developmental biology
Datasets
GEO:GSE85770
MeSH Terms
  • Animals
  • Animals, Newborn
  • Base Sequence
  • Cell Dedifferentiation
  • Heart Defects, Congenital/metabolism
  • Heart Defects, Congenital/pathology
  • Mice
  • Mutation/genetics
  • Myocytes, Cardiac/metabolism*
  • Myocytes, Cardiac/pathology
  • Organogenesis*
  • Proteolysis*
  • Rats
  • Zebrafish/genetics
  • Zebrafish/growth & development*
  • Zebrafish/metabolism*
PubMed
28211472 Full text @ Nat. Commun.
Abstract
Tissue integrity is critical for organ formation and function. During heart development, cardiomyocytes differentiate and integrate to form a coherent tissue that contracts synchronously. However, the molecular mechanisms regulating cardiac tissue integrity are poorly understood. Here we show that proteolysis, via the E3 ubiquitin ligase ASB2, regulates cardiomyocyte maturation and tissue integrity. Cardiomyocytes in asb2b zebrafish mutants fail to terminally differentiate, resulting in reduced cardiac contractility and output. Mosaic analyses reveal a cell-autonomous requirement for Asb2b in cardiomyocytes for their integration as asb2b mutant cardiomyocytes are unable to meld into wild-type myocardial tissue. In vitro and in vivo data indicate that ASB2 negatively regulates TCF3, a bHLH transcription factor. TCF3 must be degraded for cardiomyocyte maturation, as TCF3 gain-of-function causes a number of phenotypes associated with cardiomyocyte dedifferentiation. Overall, our results show that proteolysis has an important role in cardiomyocyte maturation and the formation of a coherent myocardial tissue.
Genes / Markers
Figures
Expression
Phenotype
Mutation and Transgenics
Human Disease / Model Data
Sequence Targeting Reagents
Fish
Antibodies
Orthology
Engineered Foreign Genes
Mapping
Errata and Notes