Lineage-resolved atlas of the developing human cortex

The human neocortex is composed of diverse cell types¹ that are generated during development according to spatially and temporally organized programmes initiated by neural stem cells^2-5. Despite the growing number of studies that have captured snapshots of gene expression of single cells along the axis of differentiation and maturation, the underlying map of lineage relationships that link individual progenitor cells to specific subtypes of neurons and glia remains unknown, especially in humans. Here we applied prospective lineage tracing to map the manifold of human neural stem and progenitor cell differentiation across the developmental window encompassing neurogenesis and gliogenesis in human primary tissue. By profiling the clonal output of 6,402 progenitor cells, we created a lineage-resolved map of human cortical development. Here we show that cortical progenitors switch from glutamatergic to GABAergic (involving γ-aminobutyric acid) neurogenesis around midgestation, which coincides with an onset of oligodendrocyte generation. Additionally, we find that truncated radial glia maintain a glutamatergic neurogenic potential for a protracted period during human cortical development. Unexpectedly, we find that late-born glutamatergic neurons derived from truncated radial glia exhibit molecular features of deep cortical layer neurons and may contribute to the expansion of the subplate region during midgestation.