Insulin and fibroblast growth factor 2 activate a neurogenic program in Müller glia of the chicken retina.
We have reported previously that neurotoxic damage to the chicken retina causes Müller glia to dedifferentiate, proliferate, express transcription factors common to retinal progenitors, and generate new neurons and glia, whereas the majority of newly produced cells remain undifferentiated (Fischer and Reh, 2001). Because damaged retinal cells have been shown to produce increased levels of insulin-related factors and FGFs, in the current study we tested whether intraocular injections of growth factors stimulate Müller glia to proliferate and produce new neurons. We injected growth factors and bromodeoxyuridine into the vitreous chamber of the eyes of chickens and assayed for changes in glial phenotype and proliferation within the retina. Although insulin or FGF2 alone had no effect, the combination of insulin and FGF2 caused Müller glia to coexpress transcription factors common to retinal progenitors (Pax6 and Chx10) and initiated a wave of proliferation in Müller cells that began at the retinal margin and spread into peripheral regions of the retina. Most of the newly formed cells remain undifferentiated, expressing Pax6 and Chx10, whereas some differentiate into Müller glia, and a few differentiate into neurons that express the neuronal markers Hu or calretinin. There was no evidence of retinal damage in eyes treated with insulin and FGF2. We conclude that the combination of insulin and FGF2 stimulated Müller glia to dedifferentiate, proliferate, and generate new neurons. These findings imply that exogenous growth factors might be used to stimulate endogenous glial cells to regenerate neurons in the CNS.
Fischer
Andy J
AJ
Department of Biological Structure, University of Washington, Seattle, Washington 98195, USA.
McGuire
Christopher Roger
CR
Dierks
Blair Dorian
BD
Reh
Thomas A
TA
D000818:Animals; D030161:Avian Proteins; D002453:Cell Cycle / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D002645:Chickens; D004333:Drug Administration Routes; D004357:Drug Synergism; D005136:Eye Proteins / Q000096:biosynthesis; D016222:Fibroblast Growth Factor 2 / Q000494:pharmacology*; D005974:Glutamate-Ammonia Ligase / Q000037:antagonists & inhibitors / Q000378:metabolism; D018398:Homeodomain Proteins / Q000096:biosynthesis; D007328:Insulin / Q000494:pharmacology*; D009457:Neuroglia / Q000166:cytology / Q000187:drug effects*; D009474:Neurons / Q000166:cytology / Q000187:drug effects*; D000071841:PAX6 Transcription Factor; D051761:Paired Box Transcription Factors; D012038:Regeneration / Q000187:drug effects; D012097:Repressor Proteins; D012160:Retina / Q000166:cytology / Q000187:drug effects* / Q000254:growth & development; D013234:Stem Cells / Q000166:cytology / Q000187:drug effects; D014157:Transcription Factors / Q000096:biosynthesis
D030161:Avian Proteins; D005136:Eye Proteins; D018398:Homeodomain Proteins; D007328:Insulin; D000071841:PAX6 Transcription Factor; D051761:Paired Box Transcription Factors; D012097:Repressor Proteins; D014157:Transcription Factors; D016222:Fibroblast Growth Factor 2; D005974:Glutamate-Ammonia Ligase