Generation of cellular diversity through temporal patterning of radial glia during mouse corticogenesis I

Neural cell type diversity arises from both spatial and temporal patterning of neural stem cells. Although spatial patterning mechanisms have been extensively studied, temporal patterning mechanisms remain relatively unexplored. In this study, we addressed generation of diverse neural cell types through lineage progression of mouse cortical radial glia. The time series scRNA-seq and snATAC-seq of mouse cortical development revealed that radial glia temporally transitioned from neurogenesis to gliogenesis. During gliogenic stages, various cell types were generated simultaneously along multidirectional lineage trajectories. We established comprehensive molecular maps for cortical lineage commitment and cellular diversification. The transcriptome and epigenome of cortical radial glia exhibit temporal dynamics, as revealed by scRNA-seq and snATAC-seq. Lhx2, a transcription factor with temporal dynamic chromatin binding activities, was identified as a key regulator of the neurogenesis-to-gliogenesis transition. It maintains neurogenic competence by establishing the active epigenetic state of its target genes. Overall design: Time series scRNA-seq and snATAC-seq on purified cortical progenitor. scRNA-seq on Lhx2 cKO cortical progenitor. Lhx2 CUT&Tag-seq on cortical progenitor at E13, E15, and E18. ATAC-seq, H3K4me3, H3K27me3, and Polr2a CUT&Tag-seq of control and Lhx2 cKO cortices at E15.