Stimulation of functional neuronal regeneration from Müller glia in adult mice

Jorstad, Nikolas, Wilken, Matthew, Grimes, William, Wohl, Stefanie, BandenBosch, Leah, Yoshimatsu, Takeshi, Wong, Rachel, Rieke, Fred and Reh, Thomas (2017) Stimulation of functional neuronal regeneration from Müller glia in adult mice. Nature, 548. pp. 103-107. ISSN 0028-0836

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Many retinal diseases lead to the loss of retinal neurons and cause visual impairment. The adult mammalian retina has little capacity for regeneration. By contrast, teleost fish functionally regenerate their retina following injury, and Müller glia (MG) are the source of regenerated neurons1, 2, 3, 4, 5, 6. The proneural transcription factor Ascl1 is upregulated in MG after retinal damage1, 7 in zebrafish and is necessary for regeneration8. Although Ascl1 is not expressed in mammalian MG after injury9, forced expression of Ascl1 in mouse MG induces a neurogenic state in vitro10 and in vivo after NMDA (N-methyl-D-aspartate) damage in young mice11. However, by postnatal day 16, mouse MG lose neurogenic capacity, despite Ascl1 overexpression11. Loss of neurogenic capacity in mature MG is accompanied by reduced chromatin accessibility, suggesting that epigenetic factors limit regeneration. Here we show that MG-specific overexpression of Ascl1, together with a histone deacetylase inhibitor, enables adult mice to generate neurons from MG after retinal injury. The MG-derived neurons express markers of inner retinal neurons, synapse with host retinal neurons, and respond to light. Using an assay for transposase-accessible chromatin with high-throughput sequencing (ATAC–seq), we show that the histone deacetylase inhibitor promotes accessibility at key gene loci in the MG, and allows more effective reprogramming. Our results thus provide a new approach for the treatment of blinding retinal diseases.

Item Type: Article
Schools and Departments: School of Life Sciences > Neuroscience
Research Centres and Groups: Sussex Neuroscience
Subjects: Q Science
Depositing User: Takeshi Yoshimatsu
Date Deposited: 11 Oct 2017 08:25
Last Modified: 16 Oct 2017 11:58
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