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

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

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1
Molecular and Behavioral Neuroscience Institute and Department of Biological Chemistry, University of Michigan, Ann Arbor, MI 48109, USA.

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.

PMID:
22340497
PMCID:
PMC3285435
DOI:
10.1016/j.devcel.2011.11.020
[Indexed for MEDLINE]
Free PMC Article

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