Differential effects of unfolded protein response pathways on axon injury-induced death of retinal ganglion cells.
Loss of retinal ganglion cells (RGCs) accounts for visual function deficits after optic nerve injury, but how axonal insults lead to neuronal death remains elusive. By using an optic nerve crush model that results in the death of the majority of RGCs, we demonstrate that axotomy induces differential activation of distinct pathways of the unfolded protein response in axotomized RGCs. Optic nerve injury provokes a sustained CCAAT/enhancer binding homologous protein (CHOP) upregulation, and deletion of CHOP promotes RGC survival. In contrast, IRE/XBP-1 is only transiently activated, and forced XBP-1 activation dramatically protects RGCs from axon injury-induced death. Importantly, such differential activations of CHOP and XBP-1 and their distinct effects on neuronal cell death are also observed in RGCs with other types of axonal insults, such as vincristine treatment and intraocular pressure elevation, suggesting a new protective strategy for neurodegeneration associated with axonal damage.
F.M. Kirby Neurobiology Center, Children's Hospital and Department of Neurology, Harvard Medical School, 300 Longwood Avenue, Boston, MA 02115, USA. yanghu@temple.edu
Yang
Y
Hu
Kevin K
KK
Park
Liu
L
Yang
Xin
X
Wei
Qiang
Q
Yang
Kin-Sang
KS
Cho
Peter
P
Thielen
Ann-Hwee
AH
Lee
Romain
R
Cartoni
Laurie H
LH
Glimcher
Dong Feng
DF
Chen
Zhigang
Z
He
D000596:Amino Acids; D000818:Animals; D019771:Axotomy / Q000379:methods; D053148:Caspase 3 / Q000378:metabolism; D016923:Cell Death / Q000235:genetics; D002470:Cell Survival / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D000229:Dependovirus / Q000235:genetics; D005434:Flow Cytometry; D005786:Gene Expression Regulation / Q000235:genetics / Q000502:physiology*; D005901:Glaucoma / Q000209:etiology / Q000235:genetics / Q000503:physiopathology; D049452:Green Fluorescent Proteins / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020221:Optic Nerve Injuries / Q000209:etiology / Q000473:pathology* / Q000503:physiopathology*; D017510:Protein Folding; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D000071701:Regulatory Factor X Transcription Factors; D012165:Retinal Ganglion Cells / Q000473:pathology*; D051742:Transcription Factor CHOP / Q000172:deficiency; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D014404:Tubulin / Q000378:metabolism; D000071717:X-Box Binding Protein 1
D000596:Amino Acids; D004268:DNA-Binding Proteins; C497250:Ddit3 protein, mouse; D012333:RNA, Messenger; D000071701:Regulatory Factor X Transcription Factors; D014157:Transcription Factors; D014404:Tubulin; D000071717:X-Box Binding Protein 1; C000605544:Xbp1 protein, mouse; C000605545:Xbp1 protein, rat; C462941:beta3 tubulin, mouse; C098463:dolaisoleucine; D051742:Transcription Factor CHOP; D049452:Green Fluorescent Proteins; D053148:Caspase 3