Abstract
Notch signaling is known to play important roles during retinal development. Recently, Notch signaling has been shown to be active in proliferating Müller glia in acutely damaged chick retina (Hayes et al., 2007). However, the roles of Notch in mature, undamaged retina remain unknown. Thus, the purpose of this study was to determine the role of the Notch-signaling pathway in the postnatal retina. Here we show that components of the Notch-signaling pathway are expressed in most Müller glia at low levels in undamaged retina. The expression of Notch-related genes varies during early postnatal development and across regions, with higher expression in peripheral versus central retina. Blockade of Notch activity with a small molecule inhibitor before damage was protective to retinal interneurons (amacrine and bipolar cells) and projection neurons (ganglion cells). In the absence of damage, Notch is upregulated in retinas treated with insulin and FGF2; the combination of these factors is known to stimulate the proliferation and dedifferentiation of Müller glia (Fischer et al., 2002b). Inhibition of Notch signaling during FGF2 treatment reduces levels of the downstream effectors of the MAPK-signaling pathway-p38 MAPK and pCREB in Müller glia. Further, inhibition of Notch activity potently inhibits FGF2-induced proliferation of Müller glia. Together, our data indicate that Notch signaling is downstream of, and is required for, FGF2/MAPK signaling to drive the proliferation of Müller glia. In addition, our data suggest that low levels of Notch signaling in Müller glia diminish the neuroprotective activities of these glial cells.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Amacrine Cells / drug effects
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Amacrine Cells / metabolism
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Animals
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Basic Helix-Loop-Helix Transcription Factors / genetics
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Basic Helix-Loop-Helix Transcription Factors / metabolism
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Cell Proliferation / drug effects*
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Cell Survival / physiology
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Chickens
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Cyclic AMP Response Element-Binding Protein / metabolism
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Cytoprotection / drug effects
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Cytoprotection / physiology*
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Enzyme Inhibitors / pharmacology
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Fibroblast Growth Factor 2 / metabolism
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Fibroblast Growth Factor 2 / pharmacology
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Gene Expression Regulation / drug effects
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Gene Expression Regulation / physiology
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Homeodomain Proteins / genetics
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Homeodomain Proteins / metabolism
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MAP Kinase Signaling System / drug effects
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MAP Kinase Signaling System / physiology
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Neuroglia / cytology
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Neuroglia / drug effects
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Neuroglia / metabolism*
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RNA, Messenger / drug effects
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RNA, Messenger / metabolism
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Receptors, Notch / antagonists & inhibitors
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Receptors, Notch / genetics
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Receptors, Notch / metabolism*
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Repressor Proteins / genetics
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Repressor Proteins / metabolism
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Retina / cytology
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Retina / metabolism*
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Retinal Bipolar Cells / drug effects
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Retinal Bipolar Cells / metabolism
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Retinal Ganglion Cells / drug effects
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Retinal Ganglion Cells / metabolism
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Signal Transduction / drug effects
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Signal Transduction / physiology*
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Transcription Factor HES-1
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Triglycerides / pharmacology
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gamma-Aminobutyric Acid / analogs & derivatives
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gamma-Aminobutyric Acid / pharmacology
Substances
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Basic Helix-Loop-Helix Transcription Factors
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Cyclic AMP Response Element-Binding Protein
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Enzyme Inhibitors
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Hes1 protein, mouse
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Hes5 protein, mouse
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Homeodomain Proteins
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RNA, Messenger
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Receptors, Notch
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Repressor Proteins
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Transcription Factor HES-1
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Triglycerides
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Fibroblast Growth Factor 2
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gamma-Aminobutyric Acid
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1,2-dilinolenoyl-3-(4-aminobutyryl)propane-1,2,3-triol