Regulation of cerebral cortex size and folding by expansion of basal progenitors

Abstract

Size and folding of the cerebral cortex increased massively during mammalian evolution leading to the current diversity of brain morphologies. Various subtypes of neural stem and progenitor cells have been proposed to contribute differently in regulating thickness or folding of the cerebral cortex during development, but their specific roles have not been demonstrated. We report that the controlled expansion of unipotent basal progenitors in mouse embryos led to megalencephaly, with increased surface area of the cerebral cortex, but not to cortical folding. In contrast, expansion of multipotent basal progenitors in the naturally gyrencephalic ferret was sufficient to drive the formation of additional folds and fissures. In both models, changes occurred while preserving a structurally normal, six-layered cortex. Our results are the first experimental demonstration of specific and distinct roles for basal progenitor subtypes in regulating cerebral cortex size and folding during development underlying the superior intellectual capability acquired by higher mammals during evolution.

Lentiviruses allow widespread and conditional manipulation of gene expression in the developing mouse brain

“…Nevertheless, the possibility 2821 RESEARCH REPORT Brain viral gene transfer of obtaining high and widespread infectivity and stable integration provides a practical and fast alternative to the generation of transgenic mice to investigate gene function during mammalian development. In fact, our laboratory has manipulated the same genes in neural stem cells by all three overexpression systems discussed in this study, with electroporation allowing the fast assessment of cellular effects in a small brain area, generation of transgenic mice extending this effect to the whole organ, and viral injection leading to qualitatively identical cellular effects with, in our conditions, phenotypes of even a greater magnitude than transgenic mice (Lange et al, 2009;Nonaka-Kinoshita et al, 2013).…”

Brain oxygen tension controls the expansion of outer subventricular zone-like basal progenitors in the developing mouse brain

“…Elevated neurogenesis for enlargement of the CP is dependent on the absolute number of progenitors involved. The SVZ/OSVZ is the main regulator for neocortical expansion since this is the only region that expands over the course of neurogenesis in gyrencephalic species, and particularly extensively in primates (Nonaka-Kinoshita et al, 2013;Smart et al, 2002;Stahl et al, 2013). During cortical development, early-born neurons are generated by progenitors in the VZ at E11.5-13.5 and form deeper layers, including SP, layer VI and V (Haubensak et al, 2004;Price et al, 1997).…”

“…This cell type undergoes self-renewing divisions to generate new OSVZ progenitor cells and is able to produce IPs. Interestingly, it is known that the development of this recently identified proliferative zone is responsible for the differences in brain size among mammalian species (Kriegstein et al, 2006;Nonaka-Kinoshita et al, 2013;Stahl et al, 2013). The abundance of this progenitor population is expanded in gyrencephalic species (such as primates and ferrets) and correlates with higher complexity of cortical architecture (Fietz et al, 2010;Reillo et al, 2011;Smart et al, 2002).…”

Clonal analysis reveals granule cell behaviors and compartmentalization that determine the folded morphology of the cerebellum

“…Recent studies indicate that cells with one radial process projecting to the pial surface play a key role in producing folds. In the neocortex of gyrencephalic mammals, basal radial glial cells seem to be responsible for the formation of the folds, or gyri and sulci (Nonaka-Kinoshita et al, 2013;Stahl et al, 2013). In the cerebellar cortex of mice, the base of each fissure that separates two folds (folia) has a distinct cellular organization of Bergmann glial radial fibers and associated granule cell progenitors (gcps), referred to as anchoring centers (see Fig.…”