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
  • Rats
  • Mutation/genetics
  • Myocytes, Cardiac/metabolism*
  • Myocytes, Cardiac/pathology
  • Zebrafish/genetics
  • Zebrafish/growth & development*
  • Zebrafish/metabolism*
  • Organogenesis*
  • Animals
  • Mice
  • Proteolysis*
  • Cell Dedifferentiation
  • Animals, Newborn
  • Base Sequence
  • Heart Defects, Congenital/metabolism
  • Heart Defects, Congenital/pathology
(all 16)
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
Figure Gallery (9 images)
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Expression
Phenotype
Mutations / Transgenics
Allele Construct Type Affected Genomic Region
bns33
    Small Deletion
    bns78TgTransgenic Insertion
      bns103TgTransgenic Insertion
        bns106TgTransgenic Insertion
          bns107TgTransgenic Insertion
            bns141TgTransgenic Insertion
              bns142TgTransgenic Insertion
                bns143TgTransgenic Insertion
                  bns144
                    Insertion
                    f2TgTransgenic Insertion
                      1 - 10 of 16
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                      Human Disease / Model
                      No data available
                      Sequence Targeting Reagents
                      Target Reagent Reagent Type
                      asb2a.1CRISPR1-asb2a.1CRISPR
                      asb2bCRISPR1-asb2bCRISPR
                      1 - 2 of 2
                      Show
                      Fish
                      Antibodies
                      Name Type Antigen Genes Isotypes Host Organism
                      Ab3-cdh2polyclonal
                        IgGRabbit
                        Ab-MF20monoclonal
                          IgG2bMouse
                          1 - 2 of 2
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                          Orthology
                          No data available
                          Engineered Foreign Genes
                          Marker Marker Type Name
                          DsRed2EFGDsRed2
                          EGFPEFGEGFP
                          GAL4FFEFGGAL4FF
                          GCaMPEFGGCaMP
                          GFPEFGGFP
                          mKate2EFGmKate2
                          TomatoEFGTomato
                          1 - 7 of 7
                          Show
                          Mapping
                          No data available