title: Mitogen-activated protein kinase-signaling regulates the ability of Müller glia to proliferate and protect retinal neurons against excitotoxicity.
abstract: The purpose of this study was to investigate whether insulin, fibroblast growth factor (FGF), and mitogen-activated protein kinase (MAPK) pathways protect retinal neurons against excitotoxicity and regulate the proliferation of Müller glia. We found that intraocular injections of insulin or FGF2 had variable effects upon the phosphorylation of ERK1/2, p38 MAPK, and CREB, and the expression of immediate early genes, cFos and Egr1. Accumulations of pERK1/2, p38 MAPK, pCREB, cFos and Egr1 in response to insulin or FGF2 were confined to Müller glia, whereas retinal neurons did not seem to respond to growth factors. Unlike FGF2, insulin stimulated microglia-like cells to upregulate the intermediate filament transitin and lysosomal membrane glycoprotein (LMG). With microglia-like cells and Müller glia stimulated by insulin or FGF2 there were profound effects upon numbers of dying neurons in response to excitotoxic damage. Although FGF2 significantly reduced numbers of dying neurons, insulin significantly increased numbers of dying neurons. In addition to neuroprotective affects, FGF2 also "primed" the Müller glia to proliferate following retinal damage, whereas insulin had no effect upon glial proliferation. Further, we found that FGF receptor isoform 1 (FGFR1) and FGFR3 were prominently expressed in the retina, whereas the insulin receptor and FGFR2 are not expressed, or are expressed at very low levels. We conclude that MAPK-signaling through FGF receptors stimulates Müller glia to become more neuroprotective and progenitor-like, whereas insulin acting on Müller and microglia-like cells through unidentified receptors had the opposite effect.
authors.affiliation: Department of Neuroscience, College of Medicine, The Ohio State University, Columbus, Ohio 43210-1239, USA. fischer.412@osu.edu
authors.forename: Andy J
authors.initials: AJ
authors.lastname: Fischer
authors.forename: Melissa A
authors.initials: MA
authors.lastname: Scott
authors.forename: Eric R
authors.initials: ER
authors.lastname: Ritchey
authors.forename: Patrick
authors.initials: P
authors.lastname: Sherwood
mesh_terms: D000818:Animals; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D049109:Cell Proliferation; D002645:Chickens; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D051766:Early Growth Response Protein 1 / Q000378:metabolism; D005346:Fibroblast Growth Factors / Q000378:metabolism; D007328:Insulin / Q000378:metabolism; D007381:Intermediate Filament Proteins / Q000378:metabolism; D051907:Lysosomal Membrane Proteins / Q000378:metabolism; D020935:MAP Kinase Signaling System; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000378:metabolism; D064231:Nestin; D009457:Neuroglia / Q000201:enzymology / Q000502:physiology*; D009498:Neurotoxins / Q000633:toxicity*; D010766:Phosphorylation; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D017468:Receptors, Fibroblast Growth Factor / Q000378:metabolism; D012160:Retina / Q000187:drug effects / Q000201:enzymology / Q000502:physiology; D055351:Retinal Neurons / Q000187:drug effects* / Q000201:enzymology / Q000502:physiology*; D015398:Signal Transduction; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D017362:Cyclic AMP Response Element-Binding Protein; D051766:Early Growth Response Protein 1; D007328:Insulin; D007381:Intermediate Filament Proteins; D051907:Lysosomal Membrane Proteins; D009419:Nerve Tissue Proteins; D064231:Nestin; D009498:Neurotoxins; D016760:Proto-Oncogene Proteins c-fos; D017468:Receptors, Fibroblast Growth Factor; D005346:Fibroblast Growth Factors; D048052:Mitogen-Activated Protein Kinase 3; D048051:p38 Mitogen-Activated Protein Kinases