Heterogeneity of neurons reprogrammed from spinal cord astrocytes by the proneural factors Ascl1 and Neurogenin2

Cell Rep. 2021 Jul 20;36(3):109409. doi: 10.1016/j.celrep.2021.109409.

Abstract

Astrocytes are a viable source for generating new neurons via direct conversion. However, little is known about the neurogenic cascades triggered in astrocytes from different regions of the CNS. Here, we examine the transcriptome induced by the proneural factors Ascl1 and Neurog2 in spinal cord-derived astrocytes in vitro. Each factor initially elicits different neurogenic programs that later converge to a V2 interneuron-like state. Intriguingly, patch sequencing (patch-seq) shows no overall correlation between functional properties and the transcriptome of the heterogenous induced neurons, except for K-channels. For example, some neurons with fully mature electrophysiological properties still express astrocyte genes, thus calling for careful molecular and functional analysis. Comparing the transcriptomes of spinal cord- and cerebral-cortex-derived astrocytes reveals profound differences, including developmental patterning cues maintained in vitro. These relate to the distinct neuronal identity elicited by Ascl1 and Neurog2 reflecting their developmental functions in subtype specification of the respective CNS region.

Keywords: Ascl1; Neurog2; astrocytes; direct reprogramming; patch-seq; patterning genes; single-cell RNA-seq; spinal cord.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Astrocytes / cytology*
  • Astrocytes / metabolism
  • Basic Helix-Loop-Helix Transcription Factors / metabolism*
  • Biomarkers / metabolism
  • Cellular Reprogramming*
  • Electrophysiological Phenomena
  • Mice
  • Mice, Inbred C57BL
  • Nerve Tissue Proteins / metabolism*
  • Neurons / cytology*
  • Neurons / metabolism
  • Organ Specificity
  • Spinal Cord / cytology*
  • Transcription, Genetic

Substances

  • Ascl1 protein, mouse
  • Basic Helix-Loop-Helix Transcription Factors
  • Biomarkers
  • Nerve Tissue Proteins
  • Neurog2 protein, mouse