HB-EGF Is Necessary and Sufficient for Müller Glia Dedifferentiation and Retina Regeneration

• Published in: Developmental cell Vol. 22; no. 2; pp. 334 - 347
• Main Authors: Wan, Jin, Ramachandran, Rajesh, Goldman, Daniel
• Format: Journal Article
• Language: English
• Published: Cambridge, MA Elsevier Inc 14.02.2012; Cell Press
• Subjects: Animals; Basic Helix-Loop-Helix Transcription Factors - genetics; Basic Helix-Loop-Helix Transcription Factors - metabolism; beta Catenin - genetics; beta Catenin - metabolism; Biological and medical sciences; Blotting, Western; Cell Differentiation; Cell differentiation, maturation, development, hematopoiesis; Cell physiology; Epidermal Growth Factor - pharmacology; ErbB Receptors - genetics; ErbB Receptors - metabolism; Fundamental and applied biological sciences. Psychology; 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; Molecular and cellular biology; Multipotent Stem Cells - cytology; Multipotent Stem Cells - metabolism; Neuroglia - cytology; Neuroglia - metabolism; Oligonucleotides, Antisense - pharmacology; Real-Time Polymerase Chain Reaction; Receptors, Notch - genetics; Receptors, Notch - metabolism; Regeneration; Retina - cytology; Retina - metabolism; RNA, Messenger - genetics; Signal Transduction; Wnt Proteins - genetics; Wnt Proteins - metabolism; Zebrafish; Zebrafish Proteins - genetics; Zebrafish Proteins - metabolism; Eye; Development; Hemoglobin; Visual system; Regeneration; Retina
• ISSN: 1534-5807; 1878-1551
• DOI: 10.1016/j.devcel.2011.11.020

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. [Display omitted] ► Heparin-binding epidermal-like growth factor (HB-EGF) is induced by retinal injury ► HB-EGF is necessary and sufficient to stimulate Müller glia (MG) dedifferentiation ► HB-EGF/MAPK/ASCL1a/Notch/hb-egfa signaling defines the zone of injury-responsive MG ► HB-EGF regulates progenitor proliferation via a Wnt/β-catenin-signaling pathway Using zebrafish retina regeneration as a model system, Wan et al. report that Muller glia-derived HB-EGF is necessary and sufficient for stimulating retina regeneration. HB-EGF, acting via the EGFR, stimulates MAPK and Notch signaling pathways that control Muller glia dedifferentiation and redifferentiation into retinal neurons and glia.