BMP4 and CNTF are neuroprotective and suppress damage-induced proliferation of Müller glia in the retina.
In response to acute damage, Müller glia in the chicken retina have been shown to be a source of proliferating progenitor-like cells. The secreted factors and signaling pathways that regulate this process remain unknown. The purpose of this study was to test whether secreted factors, which are known to promote glial differentiation during development, regulate the ability of Müller glia to proliferate and become retinal progenitors in response to acute damage in mature retina. We made intraocular injections of BMP4, BMP7, EGF, NGF, BDNF, or CNTF before or after a single, toxic dose of N-methyl-d-aspartate (NMDA) and assayed for proliferating progenitor-like cells within the retina. We found that injections of BMP4, BMP7, or CNTF, but not EGF, NGF, or BDNF, before NMDA treatment reduced the number of Müller glia that proliferated and gave rise to progenitor-like cells. CNTF and BMP4, but not NGF or BDNF, greatly reduced the number of cells destroyed by toxin treatment indicating that these factors protect retinal neurons from a severe excitotoxic insult. Injections of CNTF 5 days before NMDA treatment prevented neurotoxin-induced cell death and Müller glial proliferation, while injections of BMP4 had no protective effect. In addition, CNTF injected after NMDA treatment suppressed glial proliferation, while BMP4 did not. We conclude that BMP4 and CNTF, when applied before a toxic insult, act as neuroprotective agents and likely suppress the proliferative response of Müller glia to retinal damage by attenuating the retinal damage; protecting bipolar and amacrine neurons from NMDA-induced cell death. When applied after a toxic insult, CNTF suppressed glial proliferation independent of levels of retinal damage.
Fischer
Andy J
AJ
Department of Neuroscience, Ohio State University, Columbus, OH 43210-1239, USA. fischer.412@osu.edu
Schmidt
Michael
M
Schmidt
Mike
M
Omar
Ghezal
G
Reh
Thomas A
TA
D000818:Animals; D055415:Bone Morphogenetic Protein 4; D055419:Bone Morphogenetic Protein 7; D019485:Bone Morphogenetic Proteins / Q000378:metabolism* / Q000494:pharmacology; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D049109:Cell Proliferation / Q000187:drug effects; D002642:Chick Embryo; D002921:Cicatrix / Q000188:drug therapy / Q000378:metabolism / Q000517:prevention & control; D020934:Ciliary Neurotrophic Factor / Q000378:metabolism* / Q000494:pharmacology; D005911:Gliosis / Q000188:drug therapy / Q000378:metabolism* / Q000517:prevention & control; D016202:N-Methylaspartate / Q000037:antagonists & inhibitors; D009410:Nerve Degeneration / Q000188:drug therapy / Q000378:metabolism / Q000517:prevention & control; D009414:Nerve Growth Factors / Q000378:metabolism / Q000494:pharmacology; D009457:Neuroglia / Q000187:drug effects / Q000378:metabolism*; D018696:Neuroprotective Agents / Q000378:metabolism* / Q000494:pharmacology; D009498:Neurotoxins / Q000037:antagonists & inhibitors; D012160:Retina / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology; D012164:Retinal Diseases / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology; D016212:Transforming Growth Factor beta / Q000378:metabolism / Q000494:pharmacology
D055415:Bone Morphogenetic Protein 4; D055419:Bone Morphogenetic Protein 7; D019485:Bone Morphogenetic Proteins; D020934:Ciliary Neurotrophic Factor; D009414:Nerve Growth Factors; D018696:Neuroprotective Agents; D009498:Neurotoxins; D016212:Transforming Growth Factor beta; D016202:N-Methylaspartate