Molecular Identity of Human Outer Radial Glia during Cortical Development

Abstract

Summary Radial glia, the neural stem cells of the neocortex, are located in two niches: the ventricular zone and outer subventricular zone. Although outer subventricular zone radial glia may generate the majority of human cortical neurons, their molecular features remain elusive. By analyzing gene expression across single cells, we find that outer radial glia preferentially express genes related to extracellular matrix formation, migration, and stemness, including TNC, PTPRZ1, FAM107A, HOPX, and LIFR. Using dynamic imaging, immunostaining, and clonal analysis, we relate these molecular features to distinctive behaviors of outer radial glia, demonstrate the necessity of STAT3 signaling for their cell cycle progression, and establish their extensive proliferative potential. These results suggest that outer radial glia directly support the subventricular niche through local production of growth factors, potentiation of growth factor signals by extracellular matrix proteins, and activation of self-renewal pathways, thereby enabling the developmental and evolutionary expansion of the human neocortex.

From stem cells to comparative corticogenesis: a bridge too far?

“…Nevertheless macaque and human follow a common scaling law which is distinct for that observed in rodents (20). This strengthens the hypothesis that the differences in neuron production between human and other non-human primates could be merely quantitative, due to differences in the timing of the neurogenic period or in its duration for instance (21,22 (24)(25)(26)(27)(28), especially in humans where access to fresh and viable tissue is notoriously difficult (6,15). Recently, significant advances have been achieved due to the development of protocols allowing the generation of human neural rosettes (27), and human cortical organoids (25,26).…”

“…Despite a wealth of recent influential studies addressing the specific features of the human gene regulatory network of corticogenesis (1)(2)(3)(4)(5)(6)(7), the question of what makes us human is still unresolved. The human cerebral cortex has achieved a unique degree of complexity considered to underlie the emergence of unrivaled cognitive abilities compared to other species including non-human primates (8,9).…”

Single-Cell Profiling of an In Vitro Model of Human Interneuron Development Reveals Temporal Dynamics of Cell Type Production and Maturation

“…At D24, pTEL progenitor clusters expressed slightly higher levels of MKI67 and GPC3, indicating these early populations are mitotically active (Filmus, 2001;Scholzen and Gerdes, 2000). By D54 and D100, pTEL progenitor clusters express NFIA and HOPX, consistent with a transition to astrogliogenesis and/or outer radial glial cell production (Deneen et al, 2006;Pollen et al, 2015;Shu et al, 2003;Thomsen et al, 2016). After D54, pMGE clusters also express higher levels of HOPX, in addition to AQP4, S100B, ANXA1, and S100A10 compared to earlier clusters.…”

Human cerebral organoids recapitulate gene expression programs of fetal neocortex development

“…A study published while our manuscript was in review used scRNA-seq to survey the human cerebral cortex at gestational week 16-18 and reported the identification of a bRG (aka oRG) gene expression signature (29). Most of these bRG marker genes are expressed at 12-13 wpc in cells that we define as APs that highly correlate with VZ and purified aRG bulk RNAseq data.…”

“…Single-cell gene expression analysis is a powerful technique to deconstruct tissue heterogeneity and has recently been used to characterize NPC and neurons in the fetal brain (24,(27)(28)(29). Here we applied scRNA-seq to compare cell composition and lineage relationships in fetal and organoid cerebral cortex.…”