Sox11 Expression Promotes Regeneration of Some Retinal Ganglion Cell Types but Kills Others

• Published in: Neuron (Cambridge, Mass.) Mass.), 2017-06, Vol.94 (6), p.1112-1120.e4
• Main Authors: Norsworthy, Michael W., Bei, Fengfeng, Kawaguchi, Riki, Wang, Qing, Tran, Nicholas M., Li, Yi, Brommer, Benedikt, Zhang, Yiming, Wang, Chen, Sanes, Joshua R., Coppola, Giovanni, He, Zhigang
• Format: Article
• Language: English
• Subjects: Animals; Axons - metabolism; Cell Survival; Cytoskeleton; Fibroblasts; Gene expression; Gene Expression Profiling; heterogeneity; Kinases; Mice; Microscopy, Fluorescence; Nerve Regeneration - genetics; Nervous system; Neuronal Outgrowth - genetics; Neurons; Optic nerve; Optic Nerve Injuries - metabolism; Optic Nerve Injuries - pathology; Phosphatase; Proteins; PTEN Phosphohydrolase - genetics; Regeneration; Regeneration - genetics; reprogramming; Retina; Retina - metabolism; Retina - pathology; Retinal ganglion cells; Retinal Ganglion Cells - cytology; Retinal Ganglion Cells - metabolism; Retinal Ganglion Cells - pathology; RGCs; Sox11; SOXC Transcription Factors - genetics; SOXC Transcription Factors - metabolism; Stem cells; Transcription factors
• ISSN: 0896-6273; 1097-4199
• DOI: 10.1016/j.neuron.2017.05.035

At least 30 types of retinal ganglion cells (RGCs) send distinct messages through the optic nerve to the brain. Available strategies of promoting axon regeneration act on only some of these types. Here we tested the hypothesis that overexpressing developmentally important transcription factors in adult RGCs could reprogram them to a “youthful” growth-competent state and promote regeneration of other types. From a screen of transcription factors, we identified Sox11 as one that could induce substantial axon regeneration. Transcriptome profiling indicated that Sox11 activates genes involved in cytoskeletal remodeling and axon growth. Remarkably, α-RGCs, which preferentially regenerate following treatments such as Pten deletion, were killed by Sox11 overexpression. Thus, Sox11 promotes regeneration of non-α-RGCs, which are refractory to Pten deletion-induced regeneration. We conclude that Sox11 can reprogram adult RGCs to a growth-competent state, suggesting that different growth-promoting interventions promote regeneration in distinct neuronal types. •Sox11 promotes robust axon regeneration from injured adult RGCs•Sox11 re-activates a developmental axon growth program•Sox11 kills α-RGCs and promotes regeneration from other types•Pten deletion enhances axon regeneration induced by Sox11 expression Norsworthy et al. discovered that forced expression of Sox11, a transcription factor expressed in differentiating retinal progenitors, is able to reactivate an axon growth program and promote axon regeneration in subsets of adult RGCs but kills other types, suggesting that this and similar reprogramming strategies may be more complex than previously appreciated.