Gliogenesis in the outer subventricular zone promotes enlargement and gyrification of the primate cerebrum

Abstract

The primate cerebrum is characterized by a large expansion of cortical surface area, the formation of convolutions, and extraordinarily voluminous subcortical white matter. It was recently proposed that this expansion is primarily driven by increased production of superficial neurons in the dramatically enlarged outer subventricular zone (oSVZ). Here, we examined the development of the parietal cerebrum in macaque monkey and found that, indeed, the oSVZ initially adds neurons to the superficial layers II and III, increasing their thickness. However, as the oSVZ grows in size, its output changes to production of astrocytes and oligodendrocytes, which in primates outnumber cerebral neurons by a factor of three. After the completion of neurogenesis around embryonic day (E) 90, when the cerebrum is still lissencephalic, the oSVZ enlarges and contains Pax6 + /Hopx + outer (basal) radial glial cells producing astrocytes and oligodendrocytes until after E125. Our data indicate that oSVZ gliogenesis, rather than neurogenesis, correlates with rapid enlargement of the cerebrum and development of convolutions, which occur concomitantly with the formation of cortical connections via the underlying white matter, in addition to neuronal growth, elaboration of dendrites, and amplification of neuropil in the cortex, which are primary factors in the formation of cerebral convolutions in primates.cerebral cortex | brain development | corticogenesis | brain convolutions | glia C ortical development is characterized by the orderly, sequential production of neurons followed by glia, and upon their generation, these cell types must migrate long distances to their final destinations (1-5). The principal stem cells for excitatory neurons and glial cells are the radial glial cells (RGCs) whose bodies are situated in the ventricular zone (VZ) (4-6). In all mammals, including marsupials, daughter cells of RGCs give rise to progenitors that lose their apical attachment to the VZ surface and populate the subventricular zone (SVZ), which is small in rodents but much larger and more complex in carnivores and primates (7-10). In many gyrencephalic mammals, the SVZ can be divided into the inner (iSVZ) and outer (oSVZ) layers, which are separated by an inner fiber layer (IFL) and differ in terms of gene expression and complement of neural progenitor subtypes. The oSVZ compartment becomes very prominent in primates, including humans, and contains detached RGCs (11), recently renamed as outer radial glia (oRG) or basal radial glia (bRG) (5). Knowledge about the number, types, and sequences of neurons and glia generated from cortical progenitor cells is essential for understanding cortical development and evolution as well as deciphering the mechanisms of neurodevelopmental diseases, including those that affect gyrification, e.g., lissencephaly and polymicrogyria (12,13).Recently it has been postulated that the remarkable enlargement of the oSVZ and its addition of neurons to the superficial layers (III and II) is critical for the 1,000-fold expansi...

Extracellular matrix-inducing Sox9 orchestrates basal progenitor proliferation and gliogenesis in developing neocortex

“…Our findings are therefore consistent with the multi-faceted role of Sox9 in neurogenesis and gliogenesis (Cheng et al, 2009;Kaplan et al, 2017;Nagao et al, 2014;Nagao et al, 2016;Selvaraj et al, 2017;Sun et al, 2017). As neocortical expansion is characterized not only by an increase in neurogenesis, but also in gliogenesis (Rash et al, 2019), these effects of Sox9 expression again highlight the concerted nature of its action. Hence, when collectively considering the effects of Sox9 on transcription, BP proliferation and fate, and neuron production, this transcription factor shows all the hallmarks expected for a master regulator that acts in the SVZ to promote neocortical expansion.…”

“…In the developing mouse neocortex, neurogenesis and gliogenesis take place sequentially, that is, after neurogenesis, SVZ progenitors of oligodendrocytes and astrocytes are being generated (Kriegstein and Alvarez-Buylla, 2009;Merkle et al, 2004). In contrast, in the SVZ of gyrencephalic species, such as human, macaque and ferret, neurogenic and gliogenic progenitors co-exist already at the peak of neurogenesis (Martinez-Cerdeno et al, 2012;Rash et al, 2019;Reillo and Borrell, 2012;Reillo et al, 2011;Zecevic et al, 2005). We therefore have also examined the effects of conditional Sox9 expression in mouse BPs on their neurogenic vs. gliogenic fate.…”

New insights into the development of the human cerebral cortex

“…; Rash et al. ). Evolutionary changes in basal progenitor morphology, in particular an increase in process numbers, is linked to its increased proliferative capacity in humans (Kalebic et al.…”

Variance-adjusted Mahalanobis (VAM): a fast and accurate method for cell-specific gene set scoring

“…None of these other methods identified an astrocyte-related gene set. Although it is not possible to say with certainty that cluster 4 captures the glial (and potentially astrocyte-specific) sub-population in this scRNA-seq data, the top five most significantly up-regulated genes in cluster 4 according to a Wilcoxon test on the SCTransform-corrected counts all have a known association with astrocytes: Dbi [48], Ptn [49], Tubb4b [50], Hopx [51], Igfbp2 [52].…”