Heterogeneity of Neuroepithelial Cells and Radial Glia

The human cortex is comprised of diverse cell types that emerge from an initially uniform neuroepithelium that, following neural tube closure, gives rise to radial glia, the neural stem cells of the cortex. Radial glia initially reside in the ventricular zone of the cortex, and contribute to cortical expansion which is particularly pronounced in the human compared to other mammals and non-human primates. To characterize the molecular signatures of cellular subtypes that may exist at the earliest stages of neurogenesis we performed single-cell RNA-sequencing across regions of the developing human brain. We observe similar progenitor programs across brain regions that each express region-specific transcription factors. In the telencephalon, we identify nine progenitor populations, suggesting more heterogeneity among neuroepithelial cells and radial glia than previously described, including a highly prevalent mesenchymal-like population that disappears after the onset of neurogenesis. Using velocity analysis, we find that genes implicated in various neurodevelopmental diseases drive the specification and maintenance of neuroepithelial cells and radial glia. Comparison of these progenitor populations to corresponding stages of mouse development identifies two progenitor clusters that are unique to the early stages of human cortical development. Organoid systems display a low fidelity to neuroepithelial and early radial glia cell types, but this improves as neurogenesis progresses. Overall, we provide a comprehensive molecular and spatial atlas of early stages of human brain and cortical development.