Abstract
Radial glial progenitors (RGPs) give rise to the vast majority of neurons and glia in the neocortex. Although RGP behavior and progressive generation of neocortical neurons have been delineated, the exact process of neocortical gliogenesis remains elusive. Here, we report the precise progenitor behavior and gliogenesis program at single-cell resolution in the mouse neocortex. Fractions of dorsal RGPs transition from neurogenesis to gliogenesis progressively, producing astrocytes, oligodendrocytes, or both in well-defined propensities of ∼60%, 15%, and 25%, respectively, by fate-restricted "intermediate" precursor cells (IPCs). Although the total number of IPCs generated by individual RGPs appears stochastic, the output of individual IPCs exhibit clear patterns in number and subtype and form discrete local subclusters. Clonal loss of tumor suppressor Neurofibromatosis type 1 leads to excessive production of glia selectively, especially oligodendrocyte precursor cells. These results quantitatively delineate the cellular program of neocortical gliogenesis and suggest the cellular and lineage origin of primary brain tumor.
Highlights
The neocortex is a hallmark of mammals and the seat of higherorder brain functions, such as language and cognition
Mosaic analysis with double markers (MADM) analysis of neocortical gliogenesis To selectively label dorsal Radial glial progenitors (RGPs) in the developing mouse neocortex in a temporal-specific manner, we introduced the Emx1-CreERT2 transgene (Kessaris et al, 2006), which drives the selective expression of CreERT2 in RGPs in the dorsal telencephalon, into the MADM system (Gao et al, 2014; Hippenmeyer et al, 2010; Figures 1A and S1A)
Previous studies showed that RGPs switch from an amplification phase of symmetric division to a neurogenic phase of asymmetric division around embryonic day 12 (E12) (Gao et al, 2014)
Summary
The neocortex is a hallmark of mammals and the seat of higherorder brain functions, such as language and cognition. It consists of a large number of neurons and glial cells that are organized into distinct laminae. RGPs transition into a neurogenic phase in which they undergo predominantly asymmetric division, giving rise to neurons either directly or indirectly via transit amplifying progenitors, such as intermediate progenitor cells (Englund et al, 2005; Haubensak et al, 2004; Miyata et al, 2004) or outer subventricular zone RGPs ( called basal or intermediate RGPs; more abundant in primates) (Betizeau et al, 2013; Fietz et al, 2010; Hansen et al, 2010; Reillo et al, 2011; Shitamukai et al, 2011; Wang et al, 2011). Proper RGP behavior and orderly neurogenesis and neuronal migration are fundamental to neocortical development and laminar formation
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