Decoding Cortical Glial Cell Development

Abstract

Mouse cortical radial glial cells (RGCs) are primary neural stem cells that give rise to cortical oligodendrocytes, astrocytes, and olfactory bulb (OB) GABAergic interneurons in late embryogenesis. There are fundamental gaps in understanding how these diverse cell subtypes are generated. Here, by combining single-cell RNA-Seq with intersectional lineage analyses, we show that beginning at around E16.5, neocortical RGCs start to generate ASCL1+EGFR+ apical multipotent intermediate progenitors (MIPCs), which then differentiate into basal MIPCs that express ASCL1, EGFR, OLIG2, and MKI67. These basal MIPCs undergo several rounds of divisions to generate most of the cortical oligodendrocytes and astrocytes and a subpopulation of OB interneurons. Finally, single-cell ATAC-Seq supported our model for the genetic logic underlying the specification and differentiation of cortical glial cells and OB interneurons. Taken together, this work reveals the process of cortical radial glial cell lineage progression and the developmental origins of cortical astrocytes and oligodendrocytes.

Cracking the Codes of Cortical Glial Progenitors: Evidence for the Common Lineage of Astrocytes and Oligodendrocytes

“…Taken together, Li et al [7] clearly demonstrated a common lineage of cortical astrocytes and oligodendrocytes. In general, after the generation of PyNs, the cortical RGCs change their properties to aMIPCs around E16.5, and then quickly transform into proliferative bMIPCs.…”

“…In this issue, Li et al [7] took a big step forward in deciphering cortical gliogenesis with a combination of sophisticated molecular approaches. In the mouse cerebral cortex, radial glial cells (RGCs) give rise to different types of glutaminergic pyramidal neurons (PyNs) from E11.5 to E16.5 either directly or indirectly though intermediate progenitor cells (IPCs) [8].…”

“…After that, the remaining RGCs switch their properties to produce cortical oligodendrocytes, astrocytes, and olfactory bulb interneurons (OBiNs) [8]. To investigate the lineage relationship of RGCs at late prenatal stages, Li et al [7] labeled the cortical RGCs at E15.5 by introducing the pCAG-Cre plasmid into the cortical ventricular zone (VZ) of IS reporter mice (Rosa-CAG-LSL-Frt-tdTomato-Frt-EGFP) by in-utero electroporation. As expected, at postnatal day 1 (P1), the tdTomato?…”

“…Bio-informative analyses grouped these P1 cells (derived from E15. 5 Based on a combination of scRNA-Seq, scATAC-Seq, and intersectional lineage analyses, they outline a blueprint of how cortical glial cells are sequentially generated from RGCs [7]. Before E16.5, cortical RGCs primarily give rise to PyNs.…”

“…To trace the fate of Ascl1 ? MIPCs, Li et al [7] delivered pCAG-Cre plasmids into the cortical VZ of Ascl1 Flpo/Flpo ; IS embryos at E15.5 by in-utero electroporation. In this instance, the electroporated cortical RGCs and their progenies were tdTomato?.…”