Oblique Radial Glial Divisions in the Developing Mouse Neocortex Induce Self-Renewing Progenitors outside the Germinal Zone That Resemble Primate Outer Subventricular Zone Progenitors

Abstract

Radial glia cells function as neural stem cells in the developing brain and generate self-renewing and differentiating daughter cells by asymmetric cell divisions. During these divisions, the apical process or basal process of the elongated epithelial structure is asymmetrically partitioned into daughter cells, depending on developmental contexts. However, in mammalian neurogenesis, the relationship between these subcellular structures and self-renewability is largely unknown. We induced oblique cleavages of radial glia cells to split the apical and basal processes into two daughters, and investigated the fate and morphology of the daughters in slice cultures. We observed that the more basal daughter cell that inherits the basal process self-renews outside of the ventricular zone (VZ), while the more apical daughter cell differentiates. These self-renewing progenitors, termed "outer VZ progenitors," retain the basal but not the apical process, as recently reported for the outer subventricular zone (OSVZ) progenitors in primates (Fietz et al., 2010; Hansen et al., 2010); to selfrenew, they require clonal Notch signaling between sibling cells. We also found a small endogenous population of outer VZ progenitors in the mouse embryonic neocortex, consistent with a low frequency of oblique radial glia divisions. Our results describe the general role of the basal process in the self-renewal of neural progenitors and implicate the loss of the apical junctions during oblique divisions as a possible mechanism for generating OSVZ progenitors. We propose that mouse outer VZ progenitors, induced by oblique cleavages, provide a model to study both progenitor self-renewal and OSVZ progenitors.

Coevolution of radial glial cells and the cerebral cortex

“…Transitions occur at mitosis but not along the cell cycle between mitoses, when bRGCs remain stable as a single morphotype. This remarkable lineage plasticity between bRGCs and IPCs, and its apparent reversibility (bRGC‐to‐IPC, and IPC‐to‐bRGC) is in sharp contrast with current observations in mouse where the sequence aRGC‐to‐IPC or aRGC‐to‐bRGC is irreversible (Betizeau et al, 2013; Noctor et al, 2004; Shitamukai et al, 2011; Wang et al, 2011). Given that these transitions are a dynamic feature, it will require using similar videomicroscopy approaches to define if they also occur in other species, and at which frequency.…”

S‐phase duration is the main target of cell cycle regulation in neural progenitors of developing ferret neocortex

“…Highly gyrencephalic primate brains appear to have a greater variety of bRG types, and some also a higher proportion of neurogenic bIPs (Betizeau et al, 2013; Hansen et al, 2010), compared with the less gyrated ferret brain (Gertz et al, 2014; Reillo and Borrell, 2012; Reillo et al, 2011; present study), which in turn presents a greater proportion of bRG and proliferative bIPs than the lissencephalic mouse (Arai et al, 2011; Shitamukai et al, 2011; Wang et al, 2011). Interestingly, the marmoset, a near‐lissencephalic primate, displays a lower proportion of Tbr2+ mitoses than the ferret (Kelava et al, 2012).…”

“…They normally undergo self‐renewing divisions, either symmetric or asymmetric, generating neurons (as is the case in the mouse: Shitamukai et al, 2011; Wang et al, 2011) or other progenitor types (as in human and ferret: Gertz et al, 2014; Hansen et al, 2010; LaMonica et al, 2013). A recent report has described great morphologic variability in primate bRG: they can present or grow either a single process or two, directed apically and/or basally and not necessarily contacting the apical or basal surfaces of the cortical wall (Betizeau et al, 2013).…”

“…A recent report has described great morphologic variability in primate bRG: they can present or grow either a single process or two, directed apically and/or basally and not necessarily contacting the apical or basal surfaces of the cortical wall (Betizeau et al, 2013). bRG are present in both lissencephalic and gyrencephalic species, normally in a much higher proportion in the latter (Fietz et al, 2010; Hansen et al, 2010; Kelava et al, 2012; Reillo et al, 2011; Shitamukai et al, 2011; Wang et al, 2011). They have been proposed to play a significant role in the development of gyrencephaly, both as a source of neurons and as a scaffolding element (Borrell and Reillo, 2012; Fietz and Huttner, 2011; Lui et al, 2011); however, their abundance alone does not account for the presence or absence of cortical folding (Kelava et al, 2012).…”

From sauropsids to mammals and back: New approaches to comparative cortical development

“…A third progenitor subtype is also present basally and termed the outer radial glia (oRG), due to their abundance in the outer subventricular zone of primate cortices. Despite their nomenclature, they have also been described in the inner subventricular zone (ISVZ) in differing ratios (Hansen et al, 2010; Fietz et al, 2010; Reillo et al, 2010; Betizeau et al, 2013) and bordering the intermediate zone in mice (Shitamukai et al, 2011). Radial and oRG progenitors share similarities in gene expression and in the presence of a basal process from the pia.…”