HB-EGF is necessary and sufficient for Müller glia dedifferentiation and retina regeneration

Dev Cell. 2012 Feb 14;22(2):334-47. doi: 10.1016/j.devcel.2011.11.020.

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 pax6(b). We also uncover an HB-EGF/Ascl1a/Notch/hb-egf(a)-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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

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
  • ErbB Receptors / genetics
  • ErbB Receptors / metabolism
  • 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
  • Transcription Factors
  • Wnt Proteins / genetics
  • Wnt Proteins / metabolism
  • Zebrafish
  • Zebrafish Proteins / genetics
  • Zebrafish Proteins / metabolism
  • beta Catenin / genetics
  • beta Catenin / metabolism

Substances

  • Ascl1a protein, zebrafish
  • Basic Helix-Loop-Helix Transcription Factors
  • Heparin-binding EGF-like Growth Factor
  • Intercellular Signaling Peptides and Proteins
  • Oligonucleotides, Antisense
  • RNA, Messenger
  • Receptors, Notch
  • Transcription Factors
  • Wnt Proteins
  • Zebrafish Proteins
  • beta Catenin
  • Epidermal Growth Factor
  • ErbB Receptors
  • Mitogen-Activated Protein Kinases