Efficient stimulation of retinal regeneration from Müller glia in adult mice using combinations of proneural bHLH transcription factors

作者：Levi Todd, Marcus Hooper, Alexandra K. Haugan, Connor Finkbeiner, Nikolas L. Jorstad, Nicholas Radulovich, Claire K. Wong, Phoebe C Donaldson, Wesley Jenkins, Qiang Chen, Fred Rieke, Thomas A. Reh · 发表于：Cell Reports · 年份：2021 · DOI：10.1016/j.celrep.2021.109857 · 被引用次数：163 · 研究领域：Retinal Development and Disorders、CRISPR and Genetic Engineering、RNA regulation and disease

Regenerative neuroscience aims to stimulate endogenous repair in the nervous system to replace neurons lost from degenerative diseases. Recently, we reported that overexpressing the transcription factor Ascl1 in Müller glia (MG) is sufficient to stimulate MG to regenerate functional neurons in the adult mouse retina. However, this process is inefficient, and only a third of the Ascl1-expressing MG generate new neurons. Here, we test whether proneural transcription factors of the Atoh1/7 class can further promote the regenerative capacity of MG. We find that the combination of Ascl1:Atoh1 is remarkably efficient at stimulating neurogenesis, even in the absence of retinal injury. Using electrophysiology and single-cell RNA sequencing (scRNA-seq), we demonstrate that Ascl1:Atoh1 generates a diversity of retinal neuron types, with the majority expressing characteristics of retinal ganglion cells. Our results provide a proof of principle that combinations of developmental transcription factors can substantially improve glial reprogramming to neurons and expand the repertoire of regenerated cell fates.