Cortical organoids reveal flexible radial glia lineages without the brain's niche cues
Using MADM-based clonal analysis and single-cell RNA sequencing, researchers show mouse Emx1+ radial glia progenitors in self-organizing cortical organoids lack the temporally stereotyped, linear lineage progression seen in vivo. RGPs display diverse division modes and frequent lineage restriction, producing clones with reduced neuron type diversity, yet organoids still follow a unitary RGP-to-neuron transcriptional trajectory. The data suggest that non-cell-autonomous niche cues—absent in organoids (e.g., ECM, microglia, vasculature, interneurons)—are essential to maintain faithful temporal control and clonal diversity during corticogenesis. Gliogenesis occurs after neurogenesis similarly to in vivo, but overall lineage diversity is diminished, highlighting limits of self-organization for faithfully modeling in vivo cortical development.