ZFIN ID: ZDB-PUB-120223-1
HB-EGF Is Necessary and Sufficient for Müller Glia Dedifferentiation and Retina Regeneration
Wan, J., Ramachandran, R., and Goldman, D.
Date: 2012
Source: Developmental Cell   22(2): 334-347 (Journal)
Registered Authors: Goldman, Dan
Keywords: none
MeSH Terms:
  • Animals
  • Basic Helix-Loop-Helix Transcription Factors/genetics
  • Basic Helix-Loop-Helix Transcription Factors/metabolism
  • Blotting, Western
  • Cell Differentiation*
  • Epidermal Growth Factor/pharmacology
  • Heparin-binding EGF-like Growth Factor
  • Immunoenzyme Techniques
  • In Situ Hybridization
  • Intercellular Signaling Peptides and Proteins/chemistry
  • Intercellular Signaling Peptides and Proteins/genetics
  • Intercellular Signaling Peptides and Proteins/metabolism*
  • Mitogen-Activated Protein Kinases/genetics
  • Mitogen-Activated Protein Kinases/metabolism
  • Multipotent Stem Cells/cytology
  • Multipotent Stem Cells/metabolism
  • Neuroglia/cytology*
  • Neuroglia/metabolism*
  • Oligonucleotides, Antisense/pharmacology
  • RNA, Messenger/genetics
  • Real-Time Polymerase Chain Reaction
  • Receptors, Notch/genetics
  • Receptors, Notch/metabolism
  • Regeneration*
  • Retina/cytology*
  • Retina/metabolism*
  • Signal Transduction
  • Wnt Proteins/genetics
  • Wnt Proteins/metabolism
  • Zebrafish
  • Zebrafish Proteins/genetics
  • Zebrafish Proteins/metabolism
  • beta Catenin/genetics
  • beta Catenin/metabolism
PubMed: 22340497 Full text @ Dev. Cell
FIGURES
ABSTRACT
Müller glia (MG) dedifferentiation into a cycling population of multipotent progenitors is crucial to zebrafish retina regeneration. The mechanisms underlying MG dedifferentiation are unknown. Here we report that heparin-binding epidermal-like growth factor (HB-EGF) is rapidly induced in MG residing at the injury site and that pro-HB-EGF ectodomain shedding is necessary for retina regeneration. Remarkably, HB-EGF stimulates the formation of multipotent MG-derived progenitors in the uninjured retina. We show that HB-EGF mediates its effects via an EGFR/MAPK signal transduction cascade that regulates the expression of regeneration-associated genes, like ascl1a and pax6b. We also uncover an HB-EGF/Ascl1a/Notch/hb-egfa- signaling loop that helps define the zone of injury-responsive MG. Finally, we show that HB-EGF acts upstream of the Wnt/β-catenin-signaling cascade that controls progenitor proliferation. These data provide a link between extracellular signaling and regeneration-associated gene expression in the injured retina and suggest strategies for stimulating retina regeneration in mammals.
ADDITIONAL INFORMATION