Core transcription programs controlling injury-induced neurodegeneration of retinal ganglion cells

Feng Tian; Yuyan Cheng; Songlin Zhou; Qianbin Wang; Aboozar Monavarfeshani; Kun Gao; Weiqian Jiang; Riki Kawaguchi; Qing Wang; Mingjun Tang; Ryan Donahue; Huyan Meng; Yu Zhang; Anne Jacobi; Wenjun Yan; Jiani Yin; Xinyi Cai; Zhiyun Yang; Shane Hegarty; Joanna Stanicka; Phillip Dmitriev; Daniel Taub; Junjie Zhu; Clifford J Woolf; Joshua R Sanes; Daniel H Geschwind; Zhigang He

doi:10.1016/j.neuron.2022.06.003

Core transcription programs controlling injury-induced neurodegeneration of retinal ganglion cells

Neuron. 2022 Aug 17;110(16):2607-2624.e8. doi: 10.1016/j.neuron.2022.06.003. Epub 2022 Jun 28.

Authors

Feng Tian¹, Yuyan Cheng², Songlin Zhou¹, Qianbin Wang¹, Aboozar Monavarfeshani³, Kun Gao², Weiqian Jiang¹, Riki Kawaguchi², Qing Wang², Mingjun Tang¹, Ryan Donahue¹, Huyan Meng¹, Yu Zhang¹, Anne Jacobi³, Wenjun Yan⁴, Jiani Yin², Xinyi Cai¹, Zhiyun Yang¹, Shane Hegarty¹, Joanna Stanicka¹, Phillip Dmitriev¹, Daniel Taub¹, Junjie Zhu¹, Clifford J Woolf¹, Joshua R Sanes⁵, Daniel H Geschwind⁶, Zhigang He⁷

Affiliations

¹ F.M. Kirby Neurobiology Center, Boston Children's Hospital, and Department of Neurology, Harvard Medical School, 300 Longwood Avenue, Boston, MA 02115, USA.
² Departments of Neurology, Psychiatry and Human Genetics, Semel Institute for Neuroscience and Human Behavior, David Geffen School of Medicine, UCLA, Los Angeles, CA 90095-1761, USA.
³ F.M. Kirby Neurobiology Center, Boston Children's Hospital, and Department of Neurology, Harvard Medical School, 300 Longwood Avenue, Boston, MA 02115, USA; Department of Molecular and Cellular Biology, Center for Brain Science, Harvard University, 52 Oxford Street, Cambridge, MA 02138, USA.
⁴ Department of Molecular and Cellular Biology, Center for Brain Science, Harvard University, 52 Oxford Street, Cambridge, MA 02138, USA.
⁵ Department of Molecular and Cellular Biology, Center for Brain Science, Harvard University, 52 Oxford Street, Cambridge, MA 02138, USA. Electronic address: sanesj@mcb.harvard.edu.
⁶ Departments of Neurology, Psychiatry and Human Genetics, Semel Institute for Neuroscience and Human Behavior, David Geffen School of Medicine, UCLA, Los Angeles, CA 90095-1761, USA. Electronic address: dhg@mednet.ucla.edu.
⁷ F.M. Kirby Neurobiology Center, Boston Children's Hospital, and Department of Neurology, Harvard Medical School, 300 Longwood Avenue, Boston, MA 02115, USA. Electronic address: zhigang.he@childrens.harvard.edu.

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.

Keywords: ATF3; ATF4; C/EBPg; CHOP; axon regeneration and neuronal degeneration; optic nerve; retinal ganglion cell.

Publication types

Research Support, U.S. Gov't, Non-P.H.S.
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Axons / metabolism
Mice
Mice, Inbred C57BL
Nerve Regeneration / physiology
Optic Nerve Injuries* / metabolism
Retinal Ganglion Cells* / physiology

Abstract

Publication types

MeSH terms

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