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

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 to 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 axon regeneration in vivo, indicating that mechanistic analysis can be used to identify novel methods for promoting regeneration of injured neurons. ### Competing Interest Statement J.R.S. is a consultant for Biogen. Z.H. is an advisor of SpineX, Life Biosciences, and Myro Therapeutics.