title: CNTF induces photoreceptor neuroprotection and Müller glial cell proliferation through two different signaling pathways in the adult zebrafish retina.
abstract: Ciliary neurotrophic factor (CNTF) acts in several processes in the vertebrate retina, including neuroprotection of photoreceptors in the stressed adult retina and regulation of neuronal progenitor cell proliferation during retinal development. However, the signaling pathway it utilizes (Jak/Stat, MAPK, or Akt) in these processes is ambiguous. Because dark-adapted albino zebrafish exhibit light-induced rod and cone cell death and subsequently regenerate the lost photoreceptor cells, zebrafish should be a useful model to study the role of CNTF in both neuroprotection and neuronal progenitor cell proliferation. We therefore investigated the potential roles of CNTF in both the undamaged and light-damaged adult zebrafish retinas. Intraocular injection of CNTF suppressed light-induced photoreceptor cell death, which then failed to exhibit the regeneration response that is marked by proliferating Müller glia and neuronal progenitor cells. Inhibiting the MAPK signaling pathway, but neither the Stat3 nor Akt pathways, significantly reduced the CNTF-mediated neuroprotection of light-induced photoreceptor cell death. Intraocular injection of CNTF into non-light-treated (undamaged) eyes mimicked constant intense light treatment by increasing Stat3 expression in Müller glia followed by increasing the number of proliferating Müller glia and neuronal progenitors. Knockdown of Stat3 expression in the CNTF-injected non-light-treated retinas significantly reduced the number of proliferating Müller glia, while coinjection of CNTF with either MAPK or Akt inhibitors did not inhibit the CNTF-induced Müller glia proliferation. Thus, CNTF utilizes a MAPK-dependant signaling pathway in neuroprotection of light-induced photoreceptor cell death and a Stat3-dependant signaling pathway to stimulate Müller glia proliferation.
authors.affiliation: Department of Biological Sciences and Center for Zebrafish Research, University of Notre Dame, Notre Dame, IN 46556, USA. skassen@nd.edu
authors.forename: Sean C
authors.initials: SC
authors.lastname: Kassen
authors.forename: Ryan
authors.initials: R
authors.lastname: Thummel
authors.forename: Laura A
authors.initials: LA
authors.lastname: Campochiaro
authors.forename: Molly J
authors.initials: MJ
authors.lastname: Harding
authors.forename: Natalie A
authors.initials: NA
authors.lastname: Bennett
authors.forename: David R
authors.initials: DR
authors.lastname: Hyde
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects / Q000528:radiation effects; D020934:Ciliary Neurotrophic Factor / Q000494:pharmacology*; D020287:In Situ Nick-End Labeling; D020935:MAP Kinase Signaling System / Q000502:physiology; D009416:Nerve Regeneration / Q000187:drug effects / Q000502:physiology; D009457:Neuroglia / Q000187:drug effects* / Q000528:radiation effects; D018696:Neuroprotective Agents / Q000494:pharmacology*; D055355:Opsins / Q000378:metabolism; D010775:Photic Stimulation / Q000379:methods; D020419:Photoreceptor Cells, Vertebrate / Q000187:drug effects* / Q000378:metabolism; D011832:Radiation Injuries / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D012160:Retina / Q000166:cytology / Q000187:drug effects / Q000528:radiation effects; D012164:Retinal Diseases / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D050796:STAT3 Transcription Factor / Q000378:metabolism / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects; D013234:Stem Cells / Q000166:cytology / Q000187:drug effects; D015027:Zebrafish
chemical_list: D020934:Ciliary Neurotrophic Factor; D018696:Neuroprotective Agents; D055355:Opsins; D050796:STAT3 Transcription Factor