July 30, 2022

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

Author(s): Feng Tian (1), Yuyan Cheng (2), Songlin Zhou (1), Qianbin Wang (1), Aboozar Monavarfeshani (3), Kun Gao (2), Weiqian Jiang (1), Riki Kawaguchi (2), Qing Wang (2), Mingjun Tang (1), Ryan Donahue (1), Huyan Meng (1), Yu Zhang (1), Anne Jacobi (3), Wenjun Yan (4), Jiani Yin (2), Xinyi Cai (1), Zhiyun Yang (1), Shane Hegarty (1), Joanna Stanicka (1), Phillip Dmitriev (1), Daniel Taub (1), Junjie Zhu (1), Clifford J Woolf (1), Joshua R Sanes (5), Daniel H Geschwind (6), Zhigang He (7)

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.

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.

PMID: 35767995 DOI: 10.1016/j.neuron.2022.06.003

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

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