PUBLICATION

Prrx1b restricts fibrosis and promotes Nrg1-dependent cardiomyocyte proliferation during zebrafish heart regeneration

Authors
de Bakker, D.E.M., Bouwman, M., Dronkers, E., Simões, F.C., Riley, P.R., Goumans, M.J., Smits, A.M., Bakkers, J.
ID
ZDB-PUB-210907-8
Date
2021
Source
Development (Cambridge, England)   148(19): (Journal)
Registered Authors
Bakkers, Jeroen
Keywords
Fibroblasts, Fibrosis, Heart regeneration, Neuregulin, Prrx1, Zebrafish
Datasets
GEO:GSE153170
MeSH Terms
  • Zebrafish
  • Transforming Growth Factor beta/metabolism
  • Animals
  • Regeneration*
  • Cell Proliferation*
  • Cells, Cultured
  • Zebrafish Proteins/genetics
  • Zebrafish Proteins/metabolism*
  • Cell Line, Tumor
  • Collagen/metabolism
  • Homeodomain Proteins/genetics
  • Homeodomain Proteins/metabolism*
  • Cell Line
  • Humans
  • Fibrosis
  • Fibroblasts/metabolism
  • Myocytes, Cardiac/metabolism*
  • Myocytes, Cardiac/pathology
  • Myocytes, Cardiac/physiology
  • Heart/physiology*
  • Neuregulin-1/metabolism
(all 21)
PubMed
34486669 Full text @ Development
Abstract
Fibroblasts are activated to repair the heart following injury. Fibroblast activation in the mammalian heart leads to a permanent fibrotic scar that impairs cardiac function. In other organisms, like zebrafish, cardiac injury is followed by transient fibrosis and scar-free regeneration. The mechanisms that drive scarring versus scar-free regeneration are not well understood. Here we show that the homeo-box containing transcription factor Prrx1b is required for scar-free regeneration of the zebrafish heart as the loss of Prrx1b results in excessive fibrosis and impaired cardiomyocyte proliferation. Through lineage tracing and single-cell RNA-sequencing we find that Prrx1b is activated in epicardial-derived cells (EPDCs) where it restricts TGF-β ligand expression and collagen production. Furthermore, through combined in vitro experiments in human fetal EPDCs and in vivo rescue experiments in zebrafish, we conclude that Prrx1 stimulates Nrg1 expression and promotes cardiomyocyte proliferation. Collectively, these results indicate that Prrx1 is a key transcription factor that balances fibrosis and regeneration in the injured zebrafish heart.
Genes / Markers
Figures
Figure Gallery (6 images)
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Expression
Phenotype
Fish Conditions Stage Phenotype Figure
TLcold damage: heartAdult
TLcold damage: heart, chemical treatment by environment: Human Heregulin-b1Adult
cz1701Tg/cz1701Tg; pd42Tg/pd42Tgcold damage: heart, chemical treatment by environment: tamoxifenAdult
cz1701Tg/cz1701Tg; pd42Tg/pd42Tgcold damage: heart, chemical treatment by environment: tamoxifenAdult
cz1701Tg/cz1701Tg; pd42Tg/pd42Tgcold damage: heart, chemical treatment by environment: tamoxifenAdult
cz1701Tg/cz1701Tg; pd42Tg/pd42Tgcold damage: heart, chemical treatment by environment: tamoxifenAdult
prrx1bel491/el491standard conditionsPrim-15
prrx1bel491/el491standard conditionsDays 7-13
prrx1bel491/el491standard conditionsAdult
prrx1bel491/el491cold damage: heartDays 7-13
1 - 10 of 21
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Mutations / Transgenics
Allele Construct Type Affected Genomic Region
cz1701TgTransgenic Insertion
    el491
      Insertion
      el558
        Small Deletion
        ox184TgTransgenic Insertion
          ox186TgTransgenic Insertion
            pd42TgTransgenic Insertion
              1 - 6 of 6
              Show
              Human Disease / Model
              No data available
              Sequence Targeting Reagents
              No data available
              Fish
              Antibodies
              Orthology
              No data available
              Engineered Foreign Genes
              Marker Marker Type Name
              CreEFGCre
              Dendra2EFGDendra2
              EGFPEFGEGFP
              mCherryEFGmCherry
              1 - 4 of 4
              Show
              Mapping
              No data available