title: mTor signaling is required for the formation of proliferating Müller glia-derived progenitor cells in the chick retina.
abstract: We investigate the roles of mTor signaling in the formation of Müller glia-derived progenitor cells (MGPCs) in the chick retina. During embryonic development, pS6 (a readout of active mTor signaling) is present in early-stage retinal progenitors, differentiating amacrine and ganglion cells, and late-stage progenitors or maturing Müller glia. By contrast, pS6 is present at low levels in a few scattered cell types in mature, healthy retina. Following retinal damage, in which MGPCs are known to form, mTor signaling is rapidly activated in Müller glia. Inhibition of mTor in damaged retinas prevented the accumulation of pS6 in Müller glia and reduced numbers of proliferating MGPCs. Inhibition of mTor had no effect on MAPK signaling or on upregulation of the stem cell factor Klf4, whereas Pax6 upregulation was significantly reduced. Inhibition of mTor potently blocked the MGPC-promoting effects of Hedgehog, Wnt and glucocorticoid signaling in damaged retinas. In the absence of retinal damage, insulin, IGF1 and FGF2 induced pS6 in Müller glia, and this was blocked by mTor inhibitor. In FGF2-treated retinas, in which MGPCs are known to form, inhibition of mTor blocked the accumulation of pS6, the upregulation of Pax6 and the formation of proliferating MGPCs. We conclude that mTor signaling is required, but not sufficient, to stimulate Müller glia to give rise to proliferating progenitors, and the network of signaling pathways that drive the formation of MGPCs requires activation of mTor.
authors.affiliation: Department of Neuroscience, College of Medicine, The Ohio State University, 4190 Graves Hall, 333 West 10th Avenue, Columbus, OH 43210-1239, USA.
authors.forename: Christopher P
authors.initials: CP
authors.lastname: Zelinka
authors.affiliation: Department of Neuroscience, College of Medicine, The Ohio State University, 4190 Graves Hall, 333 West 10th Avenue, Columbus, OH 43210-1239, USA.
authors.forename: Leo
authors.initials: L
authors.lastname: Volkov
authors.affiliation: Department of Neuroscience, College of Medicine, The Ohio State University, 4190 Graves Hall, 333 West 10th Avenue, Columbus, OH 43210-1239, USA.
authors.forename: Zachary A
authors.initials: ZA
authors.lastname: Goodman
authors.affiliation: Department of Neuroscience, College of Medicine, The Ohio State University, 4190 Graves Hall, 333 West 10th Avenue, Columbus, OH 43210-1239, USA.
authors.forename: Levi
authors.initials: L
authors.lastname: Todd
authors.affiliation: Department of Neuroscience, College of Medicine, The Ohio State University, 4190 Graves Hall, 333 West 10th Avenue, Columbus, OH 43210-1239, USA.
authors.forename: Isabella
authors.initials: I
authors.lastname: Palazzo
authors.affiliation: Department of Neuroscience, College of Medicine, The Ohio State University, 4190 Graves Hall, 333 West 10th Avenue, Columbus, OH 43210-1239, USA.
authors.forename: William A
authors.initials: WA
authors.lastname: Bishop
authors.affiliation: Department of Neuroscience, College of Medicine, The Ohio State University, 4190 Graves Hall, 333 West 10th Avenue, Columbus, OH 43210-1239, USA andrew.fischer@osumc.edu.
authors.forename: Andy J
authors.identifier: 0000-0001-6123-7405
authors.initials: AJ
authors.lastname: Fischer
mesh_terms: D000818:Animals; D002465:Cell Movement / Q000187:drug effects; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D002645:Chickens; D063928:Ependymoglial Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D016222:Fibroblast Growth Factor 2 / Q000494:pharmacology; D007328:Insulin / Q000494:pharmacology; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology; D007335:Insulin-Like Growth Factor II / Q000494:pharmacology; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008954:Models, Biological; D016202:N-Methylaspartate / Q000494:pharmacology; D009457:Neuroglia / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D000071841:PAX6 Transcription Factor / Q000378:metabolism; D051059:PTEN Phosphohydrolase / Q000037:antagonists & inhibitors / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D012160:Retina / Q000378:metabolism* / Q000473:pathology; D015398:Signal Transduction / Q000187:drug effects; D020123:Sirolimus / Q000494:pharmacology; D013234:Stem Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*
chemical_list: D016222:Fibroblast Growth Factor 2; D007328:Insulin; D007334:Insulin-Like Growth Factor I; D007335:Insulin-Like Growth Factor II; D016202:N-Methylaspartate; D000071841:PAX6 Transcription Factor; D051059:PTEN Phosphohydrolase; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D020123:Sirolimus; D058570:TOR Serine-Threonine Kinases
keywords: Müller glia; Progenitor; Regeneration; Retina; mTor