Core transcription programs controlling injury-induced neurodegeneration of retinal ganglion cells.
ATF3
ATF4
C/EBPg
CHOP
axon regeneration and neuronal degeneration
optic nerve
retinal ganglion cell
Journal
Neuron
ISSN: 1097-4199
Titre abrégé: Neuron
Pays: United States
ID NLM: 8809320
Informations de publication
Date de publication:
17 08 2022
17 08 2022
Historique:
received:
17
01
2022
revised:
10
04
2022
accepted:
03
06
2022
pubmed:
30
6
2022
medline:
23
8
2022
entrez:
29
6
2022
Statut:
ppublish
Résumé
Regulatory programs governing neuronal death and axon regeneration in neurodegenerative diseases remain poorly understood. In adult mice, optic nerve crush (ONC) injury by severing retinal ganglion cell (RGC) axons results in massive RGC death and regenerative failure. We performed an in vivo CRISPR-Cas9-based genome-wide screen of 1,893 transcription factors (TFs) to seek repressors of RGC survival and axon regeneration following ONC. In parallel, we profiled the epigenetic and transcriptional landscapes of injured RGCs by ATAC-seq and RNA-seq to identify injury-responsive TFs and their targets. These analyses converged on four TFs as critical survival regulators, of which ATF3/CHOP preferentially regulate pathways activated by cytokines and innate immunity and ATF4/C/EBPγ regulate pathways engaged by intrinsic neuronal stressors. Manipulation of these TFs protects RGCs in a glaucoma model. Our results reveal core transcription programs that transform an initial axonal insult into a degenerative process and suggest novel strategies for treating neurodegenerative diseases.
Identifiants
pubmed: 35767995
pii: S0896-6273(22)00541-4
doi: 10.1016/j.neuron.2022.06.003
pmc: PMC9391318
mid: NIHMS1816996
pii:
doi:
Types de publication
Journal Article
Research Support, U.S. Gov't, Non-P.H.S.
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
2607-2624.e8Subventions
Organisme : NEI NIH HHS
ID : R01 EY021526
Pays : United States
Organisme : NEI NIH HHS
ID : K99 EY033457
Pays : United States
Organisme : NICHD NIH HHS
ID : P50 HD105351
Pays : United States
Organisme : NEI NIH HHS
ID : F32 EY031930
Pays : United States
Organisme : NICHD NIH HHS
ID : P30 HD018655
Pays : United States
Organisme : NEI NIH HHS
ID : P30 EY012196
Pays : United States
Organisme : NINDS NIH HHS
ID : R21 NS104248
Pays : United States
Organisme : NEI NIH HHS
ID : R01 EY026939
Pays : United States
Organisme : NEI NIH HHS
ID : K99 EY032181
Pays : United States
Organisme : NEI NIH HHS
ID : R01 EY030204
Pays : United States
Commentaires et corrections
Type : CommentIn
Type : ErratumIn
Informations de copyright
Copyright © 2022 Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of interests C.J.W. is a founder of Nocion Therapeutics and QurAlis. J.R.S. is a consultant for Biogen. Z.H. is an advisor of SpineX, Life Biosciences, and Myro Therapeutics.
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