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

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.

Automated summary

The study reveals that the transcription factor DLX2 can unlock the multipotentiality of adult astrocytes, allowing them to rapidly become neural progenitor cells and differentiate into neurons, astrocytes, and oligodendrocytes. Single-cell transcriptomics and pseudotime trajectories confirm the neural stem cell-like behavior of reprogrammed astrocytes. This discovery provides insights into potential neural regeneration strategies.