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.

Lis1 mutation prevents basal radial glia-like cell production in the mouse

“…TBC1D3 expression was shown previously to reduce the expression of N-Cadherin at the ventricular surface, with concomitant decreased expression of Trnp1 and activation of the MAPK pathway (Ju et al, 2016; Stahl et al, 2013). However, the exact mechanisms initiated by these modifications remain unclear (Penisson et al, 2019) and notably we did not observe reduced N-Cadherin in our experimental conditions. It is also unclear how the N-Cadherin defects already present in Lis1 mutant cells influence these processes to prevent the generation of bRG-like cells.…”

“…bRG producing mechanisms have been associated with either alterations of mitosis spindle orientation leading to more oblique and vertical divisions (Kalebic et al, 2018; Liu et al, 2017; Wang et al, 2016; Wong et al, 2015), and/or to detachment from the apical surface via decreased cell adhesion (Ju et al, 2016; Martínez-Martínez et al, 2016; Narayanan et al, 2018; Tavano et al, 2018; Taverna et al, 2014). Many of the genes that were described to increase bRG-like cell generation induce more oblique divisions (Penisson et al, 2019), and mitotic spindle orientation is a well-described mechanism that may contribute to the fine tuning of aRG daughter cell fate (LaMonica et al, 2013; Taverna et al, 2014). Lis1 could contribute to this phenomenon by regulating dynein-dynactin complex activity (Coquelle et al, 2002; Htet et al, 2020; Wang et al, 2013), as well as actomyosin-mediated cell membrane contractility, influencing cleavage plane positioning (Moon et al, 2020).…”

“…In our mouse mutant work, only TBC1D3 is experimentally manipulated without the possibility of multiple entries into the bRG pathway. Alternatively, human cells in developing organoids are likely to express a larger battery of genes and signaling pathways involved in the generation of bRGs (Penisson et al, 2019). However, as the state of bRGs in human pathologies remains understudied, using a single gene e.g.…”

“…bRGs are rare in the rodent, but abundant in gyrencephalic species where they are localized in an outer SVZ (oSVZ). In these species, they have been shown to play a major role during cortical development (Florio et al, 2015; Hansen et al, 2010; Fietz et al, 2010; Penisson et al, 2019; Pollen et al, 2015; Reillo et al, 2011). They are highly proliferative cells and can produce neurons and IPs, but unlike rodent IPs, they have the ability to self-renew extensively, therefore constituting a renewed pool of progenitors for cortical development (Betizeau et al, 2013; Hansen et al, 2010; LaMonica et al, 2012).…”

“…Various genes and mechanisms have been described during the past decade as regulating bRG production and amplification (Penisson et al, 2019). Several models exist to study these cells in different organisms.…”