Transformation of the Radial Glia Scaffold Demarcates Two Stages of Human Cerebral Cortex Development

Abstract

The classic view of cortical development, embodied in the radial unit hypothesis highlights the ventricular radial glia (vRG) scaffold as a key architectonic feature of the developing neocortex. The scaffold includes continuous fibers spanning the thickness of the developing cortex during neurogenesis across mammals. However, we find that in humans, the scaffold transforms into a physically discontinuous structure during the transition from infragranular to supragranular neuron production. As a consequence of this transformation, supragranular layer neurons arrive at their terminal positions in the cortical plate along outer radial glia (oRG) cell fibers. In parallel, the radial glia that contact the ventricle develop a distinct “truncated” morphology and a unique gene expression profile. We propose a supragranular layer expansion hypothesis that posits a deterministic role of oRG cells in the radial and tangential expansion of supragranular layers in primates, with implications for patterns of neuronal migration, area patterning, and cortical folding.

Association of impaired neuronal migration with cognitive deficits in extremely preterm infants

“…First, in this study, we focused on neocortical neuronal migration rather than on other relevant events occurring at a later time, such as the maturation of oligodendrocytes (10) and astrocytes (11), and had to select the stage (E16.5) at which neuronal migration continues in the IZ (the future white matter) in the mouse brains (Figure 4), while having to ignore other events occurring at a later time. In the developing of human brain, neuronal migration of superficial layer neurons might continue disproportionately until the later stages of development, because of the evolutional increase in the number of superficial pyramidal layers (17,50). The second limitation of our model is the phenotypic variation associated with mild-to-severe brain injuries, which resulted in discrepancies between the early and late outcomes due to the death of the most severely affected embryos.…”

Using brain organoids to understand Zika virus-induced microcephaly

“…This provides a unique opportunity for direct investigation of structural phenotypes, such as the relationship between ZIKV infection and cortical layer thickness. Embryonic primate and human brains exhibit a well-defined outer subventricular zone (oSVZ) layer containing outer radial glial cells (oRGCs), the major progenitors believed to be responsible for primate and human cortical expansion (Lui et al, 2011;Nowakowski et al, 2016b). One forebrain organoid model recapitulates the progenitor zone organization with an oSVZ layer formed by specialized NPCs displaying the distinct molecular signature of human oRGCs .…”

Sculpting Cerebral Cortex with Serotonin in Rodent and Primate

“…Mammalian cortical circuit formation is the result of a series of sequential events that take place mainly during embryonic and early post-natal development [11][12][13][14]. These events include the proliferation, migration and differentiation of neurons and 'glial cells' that are largely governed by genetic programs but are also sensitive to environmental factors.…”

“…At the onset of cortical development, 5-HT is of maternal and placental origin [17][18][19]. Later, by embryonic day 16 (E16 in mice) [15,16,20] and by gestational week 16 (GW16 in human) [13,14], serotoninergic afferents invade the cerebral cortex and contribute to provide 5-HT locally. Not surprisingly, like in non-mammalian species, serotonin modulates neuronal proliferation, migration and differentiation.…”