Overlapping transcriptional programs promote survival and axonal regeneration of injured retinal ganglion cells

Anne Jacobi; Nicholas M Tran; Wenjun Yan; Inbal Benhar; Feng Tian; Rebecca Schaffer; Zhigang He; Joshua R Sanes

doi:10.1016/j.neuron.2022.06.002

Overlapping transcriptional programs promote survival and axonal regeneration of injured retinal ganglion cells

Neuron. 2022 Aug 17;110(16):2625-2645.e7. doi: 10.1016/j.neuron.2022.06.002. Epub 2022 Jun 28.

Authors

Anne Jacobi¹, Nicholas M Tran², Wenjun Yan³, Inbal Benhar⁴, Feng Tian⁵, Rebecca Schaffer³, Zhigang He⁶, Joshua R Sanes⁷

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; Department of Molecular and Cellular Biology, Center for Brain Science, Harvard University, 52 Oxford Street, Cambridge, MA 02138, USA.
² Department of Molecular and Cellular Biology, Center for Brain Science, Harvard University, 52 Oxford Street, Cambridge, MA 02138, USA; Department of Molecular and Human Genetics, Baylor College of Medicine, 1 Baylor Plaza, Houston, TX 77030, USA.
³ Department of Molecular and Cellular Biology, Center for Brain Science, Harvard University, 52 Oxford Street, Cambridge, MA 02138, USA.
⁴ Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
⁵ F.M. Kirby Neurobiology Center, Boston Children's Hospital, and Department of Neurology, Harvard Medical School, 300 Longwood Avenue, Boston, MA 02115, USA.
⁶ 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.
⁷ 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.

Abstract

Injured neurons in the adult mammalian central nervous system often die and seldom regenerate axons. To uncover transcriptional pathways that could ameliorate these disappointing responses, we analyzed three interventions that increase survival and regeneration of mouse retinal ganglion cells (RGCs) following optic nerve crush (ONC) injury, albeit not to a clinically useful extent. We assessed gene expression in each of 46 RGC types by single-cell transcriptomics following ONC and treatment. We also compared RGCs that regenerated with those that survived but did not regenerate. Each intervention enhanced survival of most RGC types, but type-independent axon regeneration required manipulation of multiple pathways. Distinct computational methods converged on separate sets of genes selectively expressed by RGCs likely to be dying, surviving, or regenerating. Overexpression of genes associated with the regeneration program enhanced both survival and axon regeneration in vivo, indicating that mechanistic analysis can be used to identify novel therapeutic strategies.

Keywords: CNTF; Pten; Socs3; Wt1; axonal regeneration; single-cell RNA sequencing.

Publication types

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

MeSH terms

Animals
Axons / metabolism
Cell Survival / genetics
Mammals
Mice
Nerve Regeneration / genetics
Optic Nerve Injuries* / genetics
Optic Nerve Injuries* / metabolism
Retinal Ganglion Cells* / physiology

Abstract

Publication types

MeSH terms

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