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Core transcription programs controlling injury-induced neurodegeneration of retinal ganglion cells
Feng Tian1, Yuyan Cheng2, Songlin Zhou1
1F.M. Kirby Neurobiology Center, Boston Children's Hospital, and Department of Neurology, Harvard Medical School, 300 Longwood Avenue, Boston, MA 02115, USA.
Abstract:
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.
Insights
Researchers identified key transcription factors that control neuronal death and axon regeneration after injury. Manipulating these factors protected retinal ganglion cells in a glaucoma model, offering new therapeutic strategies for neurodegenerative diseases.
Area of Science:
- Neuroscience
- Genetics
- Molecular Biology
Background:
- Neuronal death and axon regeneration are critical in neurodegenerative diseases but poorly understood.
- Optic nerve crush (ONC) in mice causes significant retinal ganglion cell (RGC) death and fails to regenerate axons.
Purpose of the Study:
- To identify transcription factors (TFs) that repress RGC survival and axon regeneration after ONC.
- To understand the regulatory programs governing neuronal response to injury.
Main Methods:
- Performed an in vivo CRISPR-Cas9 genome-wide screen of 1,893 transcription factors.
- Utilized ATAC-seq and RNA-seq to profile epigenetic and transcriptional changes in injured RGCs.
- Identified injury-responsive TFs and their downstream targets.
Main Results:
- Converged on four TFs as critical regulators of RGC survival and axon regeneration.
- ATF3/CHOP regulate innate immunity pathways; ATF4/C/EBPγ regulate intrinsic neuronal stress pathways.
- Manipulation of these TFs demonstrated neuroprotection in a glaucoma model.
Conclusions:
- Identified core transcription programs driving RGC degeneration after axonal injury.
- Revealed specific TFs (ATF3/CHOP, ATF4/C/EBPγ) as key regulators of neuronal survival and regeneration.
- Suggests novel therapeutic strategies targeting these TFs for neurodegenerative diseases like glaucoma.
