March 2012
Volume 53, Issue 14
ARVO Annual Meeting Abstract  |   March 2012
HB-EGF is a Master Regulator of Müller Glia Dedifferentiation and Retina Regeneration
Author Affiliations & Notes
  • Jin Wan
    Molecular & Behav Neurosc Inst, University of Michigan, Ann Arbor, Michigan
  • Daniel J. Goldman
    Molecular & Behav Neurosc Inst, University of Michigan, Ann Arbor, Michigan
  • Footnotes
    Commercial Relationships  Jin Wan, None; Daniel J. Goldman, None
  • Footnotes
    Support  NIH grant RO1 EY 018132
Investigative Ophthalmology & Visual Science March 2012, Vol.53, 5927. doi:
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      Jin Wan, Daniel J. Goldman; HB-EGF is a Master Regulator of Müller Glia Dedifferentiation and Retina Regeneration. Invest. Ophthalmol. Vis. Sci. 2012;53(14):5927.

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      © ARVO (1962-2015); The Authors (2016-present)

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Purpose: : 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 tested the hypothesis that heparin binding epidermal-like growth factor (HB-EGF) is a secreted MG-derived factor that stimulates MG dedifferentiation and retina regeneration.

Methods: : Eye lesions were performed by needle poke. Dividing cells were labeled with BrdU. Growth factors were delivered into the uninjured eyes' vitreous through the cornea. RT-PCR was combined with in situ hybridization and immunohistochemistry to identify the expression of regeneration-associated genes and regenerated cell types. The function of proteins induced during regeneration was explored by knocking down their expression with morpholino-modified antisense oligonucleotides introduced into the retina by electroporation.

Results: : Within 1 hr post retinal injury, HB-EGF was induced in MG residing at the injury site. Morpholino-mediated HB-EGF knockdown suppressed injury-dependent retina regeneration. Metalloproteinase inhibition suggested proHB-EGF ectodomain shedding was necessary for HB-EGF’s action in the injured retina. Remarkably, HB-EGF stimulated the formation of multipotent MG-derived progenitors in the uninjured retina. HB-EGF mediated its effects via an EGFR/MAPK signal transduction cascade that regulated the expression of regeneration-associated genes, like ascl1a and pax6b. We uncovered 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/b-catenin signaling cascade that controls progenitor proliferation.

Conclusions: : These results suggest that HB-EGF may be master regulators of MG dedifferentiation following retinal injury and MG themselves influence their regenerative capacity. This study provides the first link between extracellular signaling and regeneration-associated gene expression in the injured retina and suggests strategies for stimulating retina regeneration in mammals.

Keywords: regeneration • growth factors/growth factor receptors • glia 

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