Single-cell profiles of retinal neurons differing in resilience to injury reveal neuroprotective genes

Abstract

Neuronal types in the central nervous system differ dramatically in their resilience to injury or 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.

Single-cell analysis of human retina identifies evolutionarily conserved and species-specific mechanisms controlling development

“…We observed many transcription factors that show highly-specific expression at various stages of differentiation of each cell type in humans, display similar expression in mouse. Both human and mouse retinal ganglion cells express the well-characterized transcript markers POU4F1, POU4F2, POU6F2, ISL1, NHLH2, RXRG, EBF1 and EBF3 (Clark et al, 2019; Rheaume et al, 2018; Tran et al, 2019); Fig. 3A-D); however, human RGCs express MYC (Fig.…”

Single-Cell Analysis of Human Retina Identifies Evolutionarily Conserved and Species-Specific Mechanisms Controlling Development

“…We observed many transcription factors that show highly enriched expression at various stages of differentiation of each cell type in humans; observations largely recapitulated in mice. Both human and mouse retinal ganglion cells express the wellcharacterized transcript markers POU4F1, POU4F2, POU6F2, ISL1, NHLH2, RXRG, EBF1, and EBF3 (Clark et al, 2019;Rheaume et al, 2018;Tran et al, 2019) (Figures 3A-3D); however, human RGCs also express MYC (Figure 3D). Human horizontal cells express TFAP2A/B, ONECUT1/2, LHX1, and ESRRB, consistent with expression in mice (Figures 3E-3H; S3H; (Boije et al, 2016;Clark et al, 2019), and show considerable overlap Balasubramanian and Gan, 2014;Clark et al, 2019;Peng et al, 2020).…”

Deciphering the Genetic Code of Neuronal Type Connectivity Through Bilinear Modeling

“…Preprocessing of this data adhered to previously documented procedures [34, 35, 42]. The transcript counts within each cell were first normalized to align with the median number of the transcripts per cell, followed by a log-transformation of the normalized counts.…”