Journal
NEURON
Volume 110, Issue 16, Pages 2607-+Publisher
CELL PRESS
DOI: 10.1016/j.neuron.2022.06.003
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Funding
- Wings for Life Spinal Cord Research Foundation [K99 EY032181, EY030204-01, R01EY021526, R01EY026939]
- Dr. Miriam and Sheldon G. Adelson Medical Research Foundation
- Gilbert Family Foundation
- DoD [W81XWH-16-1-0775]
- NIH [HD018655, P30EY012196]
- Medical Technology and Enterprise Consortium
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This study reveals critical factors involved in the survival and axon regeneration of retinal ganglion cells (RGCs) following optic nerve crush injury. The identification of these factors sheds light on the understanding of neurodegenerative diseases and provides potential strategies for treatment.
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/EBP gamma 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.
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