A Role for Intermediate Radial Glia in the Tangential Expansion of the Mammalian Cerebral Cortex

Abstract

The cerebral cortex of large mammals undergoes massive surface area expansion and folding during development. Specific mechanisms to orchestrate the growth of the cortex in surface area rather than in thickness are likely to exist, but they have not been identified. Analyzing multiple species, we have identified a specialized type of progenitor cell that is exclusive to mammals with a folded cerebral cortex, which we named intermediate radial glia cell (IRGC). IRGCs express Pax6 but not Tbr2, have a radial fiber contacting the pial surface but not the ventricular surface, and are found in both the inner subventricular zone and outer subventricular zone (OSVZ). We find that IRGCs are massively generated in the OSVZ, thus augmenting the numbers of radial fibers. Fanning out of this expanding radial fiber scaffold promotes the tangential dispersion of radially migrating neurons, allowing for the growth in surface area of the cortical sheet. Accordingly, the tangential expansion of particular cortical regions was preceded by high proliferation in the underlying OSVZ, whereas the experimental reduction of IRGCs impaired the tangential dispersion of neurons and resulted in a smaller cortical surface. Thus, the generation of IRGCs plays a key role in the tangential expansion of the mammalian cerebral cortex.

Unsupervised lineage‐based characterization of primate precursors reveals high proliferative and morphological diversity in the OSVZ

“…Previous reports on human fetal cortex reported that the OSVZ was populated by two precursors types: bRG‐ basal ‐P and nonpolar IPs (Fietz et al, 2010; Hansen et al, 2010; Reillo et al, 2011; LaMonica et al, 2013; Ostrem et al, 2014). Using 1,1′‐dioctadecyl‐3,3,3′,3 (Dil) deposits on the pia, these researchers detected back‐labeled cell bodies in the OSVZ, leading them to describe only those OSVZ precursors as bRGs that possess a basal process attached to the basal membrane (Fietz et al, 2010; Hansen et al, 2010).…”

Coevolution of radial glial cells and the cerebral cortex

“…These morphotypes range from bRGCs with only a basal process, as originally described in multiple species (Fietz et al, 2010; Hansen et al, 2010; Reillo et al, 2011), to bRGCs with only an apical process, bRGCs with both a basal and an apical process (which may contact the cortical ventricular surface, as in bipolar bRGCs, or not) and even bRGCs that dynamically extend and retract apical and basal processes along the cell cycle (Fig. 1; Betizeau et al, 2013; Pilz et al, 2013).…”

“…First, the presence of a prominent OSVZ (and hence the distinction between ISVZ and OSVZ) and a high abundance of bRGCs has been observed across a wide variety of gyrencephalic mammals but in very few lisencephalic cases (Garcia‐Moreno et al, 2012; Kelava et al, 2012; Martinez‐Cerdeno et al, 2012). Second, the relative abundance of OSVZ progenitors in the embryonic cortex has a significant positive correlation with the degree of cortical folding across a variety of species (Fietz et al, 2010; Hansen et al, 2010; Kelava et al, 2012; Pilz et al, 2013; Reillo et al, 2011). Third, models combining phylogeny proximity data with index of gyrencephaly for a wide range of species conclude that lissencephaly emerged from ancestors more gyrencephalic (Kelava et al, 2012).…”

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

“…Basal radial glia (bRG) are a recently described progenitor type, defined as Pax6‐positive, Tbr2‐negative monopolar progenitors that keep a basal process throughout their cell cycle (Fietz et al, 2010; Hansen et al, 2010; Reillo et al, 2011). 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). 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).…”