A single factor elicits multilineage reprogramming of astrocytes in the adult mouse striatum

Yunjia Zhang, Boxun Li, Sergio Cananzi, Chuanhui Han, Lei Lei Wang, Yuhua Zou, Yang Xin Fu, Gary C. Hon, Chun Li Zhang

Research output: Contribution to journalArticlepeer-review

Abstract

Astrocytes in the adult brain show cellular plasticity; however, whether they have the potential to generate multiple lineages remains unclear. Here, we perform in vivo screens and identify DLX2 as a transcription factor that can unleash the multipotentiality of adult resident astrocytes. Genetic lineage tracing and time-course analyses reveal that DLX2 enables astrocytes to rapidly become ASCL1+ neural progenitor cells, which give rise to neurons, astrocytes, and oligodendrocytes in the adult mouse striatum. Single-cell transcriptomics and pseudotime trajectories further confirm a neural stem cell-like behavior of reprogrammed astrocytes, transitioning from quiescence to activation, proliferation, and neurogenesis. Gene regulatory networks and mouse genetics identify and confirm key nodes mediating DLX2-dependent fate reprogramming. These include activation of endogenous DLX family transcription factors and suppression of Notch signaling. Such reprogramming-induced multipotency of resident glial cells may be exploited for neural regeneration.

Original languageEnglish (US)
Article numbere2107339119
JournalProceedings of the National Academy of Sciences of the United States of America
Volume119
Issue number11
DOIs
StatePublished - Mar 15 2022

Keywords

  • DLX2
  • astrocytes
  • in vivo reprogramming
  • induced neural progenitor cells
  • scRNA-seq

ASJC Scopus subject areas

  • General

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