Muller glial-derived neurons from adult mice
Identifiers: SRA: SRP108524
The adult mammalian retina, like most other regions of the central nervous system, has little capacity for neuronal regeneration following injury. As a result, the loss of retinal neurons due to their degeneration leads to permanent vision loss. By contrast, the teleost fish can regenerate all neuronal cell types of the retina following injury and synaptic connections and function are restored. Several lines of evidence in birds and zebrafish have identified Müller glia (MG) as the source of the regenerated neurons. In zebrafish, the MG respond to various types of retinal injury by producing progenitor-like cells that regenerate retinal neurons. Although the molecular pathways responsible for this endogenous reprogramming phenomenon are not completely understood, the proneural transcription factor, Ascl1, is an important component. Ascl1 is normally not expressed in mature MG, but is upregulated in these cells after retinal damage. Ascl1 is necessary for neuronal regeneration in zebrafish and forced expression of Ascl1 in mouse MG induces a neurogenic state in vitro and after NMDA damage in young mice in vivo (<2 weeks postnatal); however, by post-natal day 16 the MG lose the ability to regenerate new neurons following retinal damage, even when Ascl1 is overexpressed in the cells. The loss in neurogenesis from MG in mice older than 2 weeks of age was accompanied by a reduction in chromatin accessibility, suggesting that regeneration may be limited in this system by the ability of Ascl1 to activate its target genes.These results led to the hypothesis that MG are unable to generate new neurons in adult mice because Ascl1 (or one of its downstream target transcription factors) are not able to activate transcription at critical neuronal genes. Consistent with this hypothesis, we found that MG acquire the repressive histone modification H3K27me3 at neuronal progenitor gene promoters as they mature, and at the same time show a loss in the H3K27ac modification that is characteristic of active loci. Thus, we predicted that inhibition of histone deacetylases would lead to an increase in the acetylation at these loci in adult mouse MG and promote neuronal transcription factor binding and ultimately neuronal regeneration. We have found that this is indeed the case and the combination of Ascl1 overexpression and HDACi leads to robust regeneration of retinal neurons from MG after injury.Here we present FACS-purified single-cell RNA-seq datasets from wildtype MG and reprogrammed MG-derived neurons from adult mice. We also present ATAC-seq datasets from FACS-purified wildtype MG and reprogrammed MG-derived neurons as well as Otx2 ChIP-seq. Lastly, we present ATAC-seq data from FACS-purified GRM6+ cells, which are adult retinal bipolar cells.
Mus musculus breed:Glast/Rlbp-CreER::LNL-tTA::TetO-Ascl1-GFP
External Link: /pubmed:28746305
|Mus musculus||SAMN07185887||reprogrammed_possorted_genome_bam.bam||17.9Gb||2017-06-03 00:42:10|
|Mus musculus||SAMN07185886||wt_possorted_genome_bam.bam||15.0Gb||2017-06-02 17:30:09|