title: HB-EGF is necessary and sufficient for Müller glia dedifferentiation and retina regeneration.
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.
authors.affiliation: Molecular and Behavioral Neuroscience Institute and Department of Biological Chemistry, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Jin
authors.initials: J
authors.lastname: Wan
authors.forename: Rajesh
authors.initials: R
authors.lastname: Ramachandran
authors.forename: Daniel
authors.initials: D
authors.lastname: Goldman
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism; D015153:Blotting, Western; D002454:Cell Differentiation; D004815:Epidermal Growth Factor / Q000494:pharmacology; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism; D066257:Heparin-binding EGF-like Growth Factor; D007124:Immunoenzyme Techniques; D017403:In Situ Hybridization; D036341:Intercellular Signaling Peptides and Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D020928:Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism; D039902:Multipotent Stem Cells / Q000166:cytology / Q000378:metabolism; D009457:Neuroglia / Q000166:cytology* / Q000378:metabolism*; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D051880:Receptors, Notch / Q000235:genetics / Q000378:metabolism; D012038:Regeneration; D012160:Retina / Q000166:cytology* / Q000378:metabolism*; D015398:Signal Transduction; D014157:Transcription Factors; D051153:Wnt Proteins / Q000235:genetics / Q000378:metabolism; D015027:Zebrafish; D029961:Zebrafish Proteins / Q000235:genetics / Q000378:metabolism; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D004815:Epidermal Growth Factor; D066246:ErbB Receptors; D066257:Heparin-binding EGF-like Growth Factor; D036341:Intercellular Signaling Peptides and Proteins; D020928:Mitogen-Activated Protein Kinases; D016376:Oligonucleotides, Antisense; D012333:RNA, Messenger; D051880:Receptors, Notch; D014157:Transcription Factors; D051153:Wnt Proteins; D029961:Zebrafish Proteins; D051176:beta Catenin; C468127:Ascl1a protein, zebrafish