Single-Cell Profiles of Retinal Ganglion Cells Differing in Resilience to Injury Reveal Neuroprotective Genes

Nicholas M Tran; Karthik Shekhar; Irene E Whitney; Anne Jacobi; Inbal Benhar; Guosong Hong; Wenjun Yan; Xian Adiconis; McKinzie E Arnold; Jung Min Lee; Joshua Z Levin; Dingchang Lin; Chen Wang; Charles M Lieber; Aviv Regev; Zhigang He; Joshua R Sanes

doi:10.1016/j.neuron.2019.11.006

Single-Cell Profiles of Retinal Ganglion Cells Differing in Resilience to Injury Reveal Neuroprotective Genes

Neuron. 2019 Dec 18;104(6):1039-1055.e12. doi: 10.1016/j.neuron.2019.11.006. Epub 2019 Nov 26.

Authors

Nicholas M Tran¹, Karthik Shekhar², Irene E Whitney¹, Anne Jacobi³, Inbal Benhar², Guosong Hong⁴, Wenjun Yan¹, Xian Adiconis², McKinzie E Arnold³, Jung Min Lee⁵, Joshua Z Levin², Dingchang Lin⁵, Chen Wang³, Charles M Lieber⁵, Aviv Regev⁶, Zhigang He³, Joshua R Sanes⁷

Affiliations

¹ Center for Brain Science and Department of Molecular and Cellular Biology, Harvard University, Cambridge, MA, USA.
² Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
³ F.M. Kirby Neurobiology Center, Department of Neurology, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.
⁴ Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA 02138, USA; Department of Material Science and Engineering and Wu Tsai Neurosciences Institute, Stanford University, Stanford, CA 94305, USA.
⁵ Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA 02138, USA.
⁶ Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA; Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA and Department of Biology and Koch Institute, MIT, Cambridge, MA 02139, USA.
⁷ Center for Brain Science and Department of Molecular and Cellular Biology, Harvard University, Cambridge, MA, USA. Electronic address: sanesj@mcb.harvard.edu.

Abstract

Neuronal types in the central nervous system differ dramatically in their resilience to injury or other insults. Here we studied the selective resilience of mouse retinal ganglion cells (RGCs) following optic nerve crush (ONC), which severs their axons and leads to death of ∼80% of RGCs within 2 weeks. To identify expression programs associated with differential resilience, we first used single-cell RNA-seq (scRNA-seq) to generate a comprehensive molecular atlas of 46 RGC types in adult retina. We then tracked their survival after ONC; characterized transcriptomic, physiological, and morphological changes that preceded degeneration; and identified genes selectively expressed by each type. Finally, using loss- and gain-of-function assays in vivo, we showed that manipulating some of these genes improved neuronal survival and axon regeneration following ONC. This study provides a systematic framework for parsing type-specific responses to injury and demonstrates that differential gene expression can be used to reveal molecular targets for intervention.

Publication types

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

MeSH terms

Animals
Cell Survival / genetics*
Female
Male
Mice
Nerve Crush
Nerve Regeneration / genetics*
Neuroprotection / genetics*
Retinal Ganglion Cells / physiology*

Abstract

Publication types

MeSH terms

Grants and funding