Sep 3, 2019

STAT pathway activation limits the Ascl1-mediated chromatin remodeling required for neural regeneration from Muller glia in adult mouse retina.

BioRxiv : the Preprint Server for Biology
Thomas A RehFred Rieke

Abstract

Muller glia (MG) can serve as a source for retinal regeneration in some non-mammalian vertebrates. Recently we found that this process can be induced in mouse MG after injury, by combining transgenic expression of the proneural transcription factor Ascl1 and the HDAC inhibitor TSA. However, new neurons are only generated from a subset of MG in this model, and identifying factors that limit Ascl1-mediated MG reprogramming could potentially make this process more efficient, and potentially useful clinically. One factor that limits neurogenesis in some non-mammalian vertebrates is the STAT pathway activation that occurs in MG in response to injury. In this report, we tested whether injury induced STAT activation hampers the ability of Ascl1 to reprogram MG into retinal neurons. Using a STAT inhibitor, in combination with our previously described reprogramming paradigm, we found a large increase in the ability of MG to generate neurons, similar to those we described previously. Single-cell RNA-seq showed that the progenitor-like cells derived from Ascl1-expressing MG have a higher level of STAT signaling than those that become neurons. Using Ascl1 ChIP-seq and DNase-seq, we found that developmentally inappropriate Ascl1 binding sit...Continue Reading

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Mentioned in this Paper

Single-Cell Analysis
Study
Neurons
Inhibitors
Neuroglia
Plants, Transgenic
Nerve Regeneration
Cellular Reprogramming
ASCL1
Retina

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