Abstract
Müller glia in the mature retina have the capacity to become progenitor-like cells in a many different vertebrate classes. The cell-signaling pathways that control the ability of mature Müller glia to become progenitor-like cells remain uncertain. The purpose of this study was to investigate the roles of the Mitogen-Activated Protein Kinase (MAPK) pathway in regulating the activity of Müller glia in the chicken retina. In response to acute retinal damage, we found that Müller glia accumulated phosphorylated ERK1/2 and phospho-CyclicAMP Response Element Binding-protein (pCREB), and transiently expressed immediate early genes, cFos and Egr1, that are known to be downstream of MAPK-signaling. Egr1 and pCREB were normally expressed by retinal progenitors in the circumferential marginal zone (CMZ), whereas cFos and pERK1/2 were not. In addition, small molecule inhibitors of MEK (UO126) and the FGF-receptor (SU5402) suppressed the proliferation of Müller glia-derived progenitor-like cells. These inhibitors suppressed the accumulation of Egr1 and pCREB, whereas levels of cFos were unaffected in the glial cells. These findings suggest that Egr1 and pCREB are downstream of the signaling cascade activated by FGF-receptors and ERK1/2. Further, our findings suggest that Egr1 and pCREB may promote glial proliferation. We propose that activation of both the FGF-receptor and ERK1/2-pathway is required for the proliferation and transdifferentiation of Müller glia into progenitor-like cells.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Animals
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Butadienes / pharmacology
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Cell Differentiation / drug effects
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Cell Differentiation / physiology
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Cell Proliferation / drug effects*
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Chickens
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Cyclic AMP Response Element-Binding Protein / drug effects
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Cyclic AMP Response Element-Binding Protein / metabolism
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Early Growth Response Protein 1 / genetics
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Early Growth Response Protein 1 / metabolism
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MAP Kinase Kinase 1 / antagonists & inhibitors
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MAP Kinase Kinase 1 / metabolism
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MAP Kinase Signaling System / drug effects
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MAP Kinase Signaling System / physiology*
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Mitogen-Activated Protein Kinase 3 / drug effects
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Mitogen-Activated Protein Kinase 3 / metabolism
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Nerve Regeneration / drug effects
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Nerve Regeneration / physiology
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Neurogenesis / drug effects
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Neurogenesis / physiology
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Neuroglia / cytology
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Neuroglia / drug effects
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Neuroglia / enzymology*
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Nitriles / pharmacology
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Proto-Oncogene Proteins c-fos / genetics
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Proto-Oncogene Proteins c-fos / metabolism
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Pyrroles / pharmacology
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Receptors, Fibroblast Growth Factor / antagonists & inhibitors
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Receptors, Fibroblast Growth Factor / metabolism
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Retina / cytology
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Retina / enzymology*
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Retina / injuries*
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Retinal Diseases / drug therapy
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Retinal Diseases / enzymology*
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Retinal Diseases / physiopathology
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Stem Cells / cytology
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Stem Cells / drug effects
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Stem Cells / enzymology*
Substances
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Butadienes
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Cyclic AMP Response Element-Binding Protein
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Early Growth Response Protein 1
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Nitriles
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Proto-Oncogene Proteins c-fos
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Pyrroles
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Receptors, Fibroblast Growth Factor
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SU 5402
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U 0126
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Mitogen-Activated Protein Kinase 3
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MAP Kinase Kinase 1