Injury-induced ASCL1 expression orchestrates a transitory cell state required for repair of the neonatal cerebellum.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 34878841.
- Also identified by DOI 10.1126/sciadv.abj1598 and PMC identifier 8654303.
- Licence recorded as CC BY.
- The licence permits redistribution, so the abstract is shown in full and the full text is available from the publisher.
Abstract
To understand repair processes, it is critical to identify the molecular foundations underlying progenitor diversity and plasticity. Upon injury to the neonatal cerebellum, a normally gliogenic <i>nestin</i>-expressing progenitor (NEP) in the Bergmann glia layer (BgL) undergoes adaptive reprograming to restore granule cell production. However, the cellular states and genes regulating the NEP fate switch are unknown. Using single-cell RNA sequencing and fate mapping, we defined molecular subtypes of NEPs and their lineages under homeostasis and repair. NEPs contain two major subtypes: <i>Hopx</i><sup>+</sup> astrogliogenic and <i>Ascl1</i><sup>+</sup> neurogenic NEPs that are further subdivided based on their location, lineage, and differentiation status. Upon injury, an <i>Ascl1</i><sup>+</sup> transitory cellular state arises from <i>Hopx</i><sup>+</sup> BgL-NEPs. Furthermore, mutational analysis revealed that induction of <i>Ascl1</i> is required for adaptive reprogramming by orchestrating a glial-to-neural switch in vivo following injury. Thus, we provide molecular and cellular insights into context-dependent progenitor plasticity and repair mechanisms in the brain.