Mouse cortical radial glial cells (RGCs) are primary neural stem cells that give rise to cortical oligodendrocytes, astrocytes, and olfactory bulb (OB) GABAergic interneurons in late embryogenesis. There are fundamental gaps in understanding how these diverse cell subtypes are generated. Here, by combining single-cell RNA-Seq with intersectional lineage analyses, we show that beginning at around E16.5, neocortical RGCs start to generate ASCL1+EGFR+ apical multipotent intermediate progenitors (MIPCs), which then differentiate into basal MIPCs that express ASCL1, EGFR, OLIG2, and MKI67. These basal MIPCs undergo several rounds of divisions to generate most of the cortical oligodendrocytes and astrocytes and a subpopulation of OB interneurons. Finally, single-cell ATAC-Seq supported our model for the genetic logic underlying the specification and differentiation of cortical glial cells and OB interneurons. Taken together, this work reveals the process of cortical radial glial cell lineage progression and the developmental origins of cortical astrocytes and oligodendrocytes.

SUMMARY Striatal medium-sized spiny neurons (MSNs), composed of striatonigral and striatopallidal neurons, are derived from the lateral ganglionic eminence (LGE). We find that the transcription factor Sp9 is expressed in LGE progenitors that generate nearly all striatal MSNs, and that Sp9 expression is maintained in postmitotic striatopallidal MSNs. Sp9 null mice lose most striatopallidal MSNs due to decreased proliferation of striatopallidal MSN progenitors and increased Bax-dependent apoptosis, whilethe development of striatonigral neurons is largely unaffected. ChIP-qPCR provides evidence that Ascl1 directly binds the Sp9 promoter. RNA-Seq and in situ hybridization reveal that Sp9 promotes expression of Adora2a, P2ry1, Gpr6 and Grik3 in the LGE and striatum. Thus, Sp9 is crucial for the generation, differentiation and survival of striatopallidal MSNs.

Dopamine receptor DRD1-expressing medium spiny neurons (D1 MSNs) and dopamine receptor DRD2-expressing medium spiny neurons (D2 MSNs) are the principal projection neurons in the striatum, which is divided into dorsal striatum (caudate nucleus and putamen) and ventral striatum (nucleus accumbens and olfactory tubercle). Progenitors of these neurons arise in the lateral ganglionic eminence (LGE). Using conditional deletion, we show that mice lacking the transcription factor genes and lose virtually all D2 MSNs as a result of reduced neurogenesis in the LGE, whereas D1 MSNs are largely unaffected. SP8 and SP9 together drive expression of the transcription factor in a spatially restricted domain of the LGE subventricular zone. Conditional deletion of also prevents the formation of most D2 MSNs, phenocopying the mutants. Finally, ChIP-Seq reveals that SP9 directly binds to the promoter and a putative enhancer of Thus, this study defines components of a transcription pathway in a regionally restricted LGE progenitor domain that selectively drives the generation of D2 MSNs.