Mouse Cortical Cellular Diversification Through Lineage Progression of Radial Glia

Cortical radial glia (RGs) sequentially generate pyramidal neurons (PyNs) and glia. In this study, we investigated the molecular logic underlying cortical cellular diversification using time-series scRNA-seq and snATAC-seq on FlashTag- or hGFAP-GFP-labeled mouse cortical progenitors across embryonic and postnatal stages. Our data revealed that RGs transition from early to late over time, sequentially producing intermediate neuronal progenitors (INPs) and intermediate glial progenitors (IGPs). While INPs expand exclusively to generate PyNs, IGPs progress from young to old, sequentially producing cortical astrocytes, oligodendrocytes, and olfactory bulb interneurons. We constructed comprehensive molecular maps that reflect cell lineage progression. Our study reveals that chromatin accessibility drives cellular diversification by restricting broadly expressed transcription factors to specific stages and cell types. For instance, Lhx2 , which is constantly expressed in RGs across all stages, exhibits reduced DNA-binding activity as development progresses. Lhx2 maintains neurogenic competence by establishing an active epigenetic state at neurogenic genes. As RGs transition to later stages, the chromatin regions bound by Lhx2 become inaccessible, leading to the loss of neurogenic competence and the acquisition of gliogenic competence.