In vivo analysis of Ascl1 defined progenitors reveals distinct developmental dynamics during adult neurogenesis and gliogenesis

In the adult mammalian brain, new neurons and glia are continuously generated but molecular factors regulating their differentiation and lineage relationships are largely unknown. We show that Ascl1, a bHLH ( basic helix-loop-helix) transcription factor, transiently labels neuronal and oligodendrocyte precursors in the adult brain. Using in vivo lineage tracing with inducible Cre recombinase, we followed the maturation of these precursors in four distinct regions. In the hippocampus, Ascl1 mostly marks type-2a progenitor cells with some late stage type-1 stem cells. Thirty days after Ascl1 expression, although a majority of the cells matured to granule neurons, a few cells remained as immature progenitors. By 6 months, however, essentially all Ascl1 lineage cells were granule neurons. In contrast, in the olfactory bulb neuronal lineage, Ascl1 is restricted to transit amplifying cells, and by 30 d all cells matured into GABAergic interneurons. Ascl1 also broadly marks oligodendrocyte precursors in subcortical gray and white matter regions. In the corpus callosum, Ascl1 defines a ventral layer of early oligodendrocyte precursors that do not yet express other early markers of this lineage like PDGFR alpha and Olig2. By 30 d, most had transitioned to mature oligodendrocytes. In contrast, Ascl1 expressing oligodendrocyte precursors in gray matter already coexpressed the early oligodendrocyte markers, but by 30 d they mostly remained as precursors. Our results reveal that Ascl1 is a common molecular marker of early progenitors of both neurons and oligodendrocytes in the adult brain, and these Ascl1 defined progenitors mature with distinct dynamics in different brain regions.