Journal Article

Stimulation of functional neuronal regeneration from Müller glia in adult mice

Wong, Rachel O., Jorstad, Nikolas L., Reh, Thomas A., Wohl, Stefanie G., VandenBosch, Leah S., Wilken, Matthew S., Rieke, Fred, Grimes, William N., Yoshimatsu, Takeshi

2017

Overview

Inhibition of histone deacetylation allows the transcription factor Ascl1 to bind to key gene loci in Müller glia and drive the functional generation of retinal neurons in adult mice. Retina regeneration in rodents Fish, birds and reptiles maintain the capacity to regenerate functional retinal neurons after injury, yet this form of regeneration does not occur in adult mammals. Humans can suffer from a significant number of diseases involving the loss of vision due to retinal disease and damage, so understanding why adult mammals lack this regenerative capacity is crucial. Here, Thomas Reh and colleagues express transcription factor Ascl1, previously known to enhance retinal neuron regeneration in fish, in Müller glia cells of rodents. Ascl1 was only able to drive functional generation of new retinal neurons in adult mice in conjunction with the inhibition of histone deacetylase (HDAC) inhibitors. The HDAC inhibitors enabled Ascl1 to bind at key gene loci in the Müller glia, allowing for the reprogramming of these cells to retinal neurons. 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 neurons 1 , 2 , 3 , 4 , 5 , 6 . The proneural transcription factor Ascl1 is upregulated in MG after retinal damage 1 , 7 in zebrafish and is necessary for regeneration 8 . Although Ascl1 is not expressed in mammalian MG after injury 9 , forced expression of Ascl1 in mouse MG induces a neurogenic state in vitro 10 and in vivo after NMDA ( N -methyl- d -aspartate) damage in young mice 11 . However, by postnatal day 16, mouse MG lose neurogenic capacity, despite Ascl1 overexpression 11 . 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.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 38/1 / 38/39 / 38/91 / 631/136/368 / 631/378/1687 / 64/110 / 96/63 / Animals / ASCL1 protein / Basic Helix-Loop-Helix Transcription Factors - genetics / Basic Helix-Loop-Helix Transcription Factors - metabolism / Chromatin / Enzymes / Epistasis, Genetic - drug effects / Eye diseases / Female / Glutamate receptors / Histone deacetylase / Histone Deacetylase Inhibitors - pharmacology / Humanities and Social Sciences / Hydroxamic Acids - pharmacology / In vitro methods and tests / Inhibitors / Injuries / letter / Male / Mammals / Mice / Morphology / multidisciplinary / N-Methyl-D-aspartic acid / Nerve Regeneration - drug effects / Neural Pathways - drug effects / Neurogenesis / Neurogenesis - drug effects / Neuroglia - cytology / Neuroglia - metabolism / Neuronal-glial interactions / Neurons / Neurons - cytology / Neurons - drug effects / Neurons - metabolism / Next-generation sequencing / Proteins / Regeneration / Retina / Retina - cytology / Retina - metabolism / Science / Stem cells / Stimulation / Synapses / Synapses - drug effects / Synapses - metabolism / Transposase / Visual perception