Genes and Mechanisms Involved in the Generation and Amplification of Basal Radial Glial Cells

Abstract

The development of the cerebral cortex relies on different types of progenitor cell. Among them, the recently described basal radial glial cell (bRG) is suggested to be of critical importance for the development of the brain in gyrencephalic species. These cells are highly numerous in primate and ferret brains, compared to lissencephalic species such as the mouse in which they are few in number. Their somata are located in basal subventricular zones in gyrencephalic brains and they generally possess a basal process extending to the pial surface. They sometimes also have an apical process directed toward the ventricular surface, similar to apical radial glial cells (aRGs) from which they are derived, and whose somata are found more apically in the ventricular zone. bRGs share similarities with aRGs in terms of gene expression (SOX2, PAX6, and NESTIN), whilst also expressing a range of more specific genes (such as HOPX). In primate brains, bRGs can divide multiple times, self-renewing and/or generating intermediate progenitors and neurons. They display a highly specific cytokinesis behavior termed mitotic somal translocation. We focus here on recently identified molecular mechanisms associated with the generation and amplification of bRGs, including bRG-like cells in the rodent. These include signaling pathways such as the FGF-MAPK cascade, SHH, PTEN/AKT, PDGF pathways, and proteins such as INSM, GPSM2, ASPM, TRNP1, ARHGAP11B, PAX6, and HIF1α. A number of these proteins were identified through transcriptome comparisons in human aRGs vs. bRGs, and validated by modifying their activities or expression levels in the mouse. This latter experiment often revealed enhanced bRG-like cell production, even in some cases generating folds (gyri) on the surface of the mouse cortex. We compare the features of the identified cells and methods used to characterize them in each model. These important data converge to indicate pathways essential for the production and expansion of bRGs, which may help us understand cortical development in health and disease.

Keywords: adhesion; basal radial glia; cell division; cortical development; neural progenitor cells; signaling pathways; spindle orientation.

FIGURE 1

Schematic view of the development of the embryonic neocortex. VZ, ventricular zone; iSVZ, inner subventricular zone; oSVZ, outer subventricular zone; IZ, intermediate zone; CP, cortical plate; MZ, marginal zone. aRG, apical radial glial cell; bRGs, basal radial glial cells (different bRG morphotypes are shown); IP, intermediate progenitor. In the key, common genetic markers are cited with each cell type.

FIGURE 2

Putative model describing the signaling pathways and other genes suggested to be involved in bRG generation. Canonical pathways currently demonstrated to promote bRG production include the FGF-MAPK axis, PDGFD signaling, PTEN/AKT/mTOR, and SHH pathways. Human/hominoid specific genes depicted in this figure include TBC1D3, a RABGAP protein that promotes Erk signaling and appears to repress Trnp1 expression, and TMEM14B, a transmembrane protein that promotes IQGAP1 translocation to the nucleus to regulate cell cycle progression. ARHGAP11B and Aspm are not indicated here as their function are either unclear or they do not obviously fit in the pathways with current knowledge. AJ, adherens junction; ECM, extracellular matrix.

FIGURE 3

Mechanisms and genes associated with bRG generation/amplification. (A) List of genes demonstrated to be associated with cellular mechanisms (aRG maintenance or depletion, mitotic spindle orientation, and cell adhesion) leading to bRG generation. (B) List of genes or treatments leading to differential basal progenitor pool expansion and apparition of folds in the mouse (TBC1D3 FE, Trnp1 KD, and TMEM14B) or human organoids (AKT signaling) or modified folding in the ferret (ARHGAP11B FE, FGF signaling). FE, forced expression; KD, knockdown; LOF, loss of function; DN, dominant-negative.