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Review
. 2016 May 17;35(10):1021-44.
doi: 10.15252/embj.201593701. Epub 2016 Apr 7.

Cerebral cortex expansion and folding: what have we learned?

Virginia Fernández  1 , Cristina Llinares-Benadero  1 , Víctor Borrell  2
Affiliations
Review

Cerebral cortex expansion and folding: what have we learned?

Virginia Fernández et al. EMBO J. .

Abstract

One of the most prominent features of the human brain is the fabulous size of the cerebral cortex and its intricate folding. Cortical folding takes place during embryonic development and is important to optimize the functional organization and wiring of the brain, as well as to allow fitting a large cortex in a limited cranial volume. Pathological alterations in size or folding of the human cortex lead to severe intellectual disability and intractable epilepsy. Hence, cortical expansion and folding are viewed as key processes in mammalian brain development and evolution, ultimately leading to increased intellectual performance and, eventually, to the emergence of human cognition. Here, we provide an overview and discuss some of the most significant advances in our understanding of cortical expansion and folding over the last decades. These include discoveries in multiple and diverse disciplines, from cellular and molecular mechanisms regulating cortical development and neurogenesis, genetic mechanisms defining the patterns of cortical folds, the biomechanics of cortical growth and buckling, lessons from human disease, and how genetic evolution steered cortical size and folding during mammalian evolution.

Keywords: evolution; ferret; gyrencephaly; humans; neocortex.

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Figures

Figure 1
Figure 1. Stem cells in the developing cerebral cortex of gyrencephalic brains and their molecular regulation
Schema depicting the main types of progenitor cells and their lineage relationships in the developing cerebral cortex. Arrows indicate lineage relationships demonstrated by time‐lapse imaging and/or by retroviral lineage tracing. During the expansion phase, most neuroepithelial cells divide symmetrically to self‐amplify to generate apical radial glial cells. During the neurogenic phase, most aRGCs divide asymmetrically to generate neurons, either directly or indirectly through intermediate progenitor cells or basal radial glial cells. Molecules or pathways regulating some of these steps are indicated. MZ, marginal zone; CP, cortical plate; IZ, intermediate zone; SVZ, subventricular zone; VZ, ventricular zone.
Figure 2
Figure 2. Patterns of cell division in the embryonic cerebral cortex and mechanisms for tangential versus radial expansion
(A) Two patterns of cortical progenitor cell division with opposite neurogenic outcome: The total number of neurons produced is proportional to the generation of intermediate progenitor cells, very small in species with a smooth cortex (left) and large in species with a folded cortex (right). (B) Difference in the general arrangement of the radial fiber scaffold in the cerebral cortex undergoing tangential (left) versus radial expansion (right). In species with a smooth cortex like mouse (left), radial glial fibers are parallel (green) and there is no net lateral dispersion of radially migrating neurons (yellow) with respect to the positions of their progenitor aRGCs (green). In gyrencephalic species, the radial fiber scaffold becomes divergent due to the intercalation of radial fibers from bRGCs. As a result, radially migrating neurons follow divergent trajectories which cause their lateral dispersion; this increases cortical surface area and ultimately promotes folding (modified from Borrell & Reillo, 2012).
Figure 3
Figure 3. Patterns of gene expression map the prospective location of cortical folds in the developing ferret brain
(A) Schema of sagittal sections of ferret brains at postnatal day P6 showing the modular pattern of mRNA expression for Eomes at the outer subventricular zone (shaded areas). (B, C) Representation of the ferret brain surface at postnatal day P2 (B) and adult (C) overlapped with the map of Eomes expression modules (shaded) and prospective gyri (striped pattern), showing the spatial correlation between Eomes expression and gyri (adapted from de Juan Romero et al, 2015).
Figure 4
Figure 4. Human cortical malformations and their phenotypic manifestations
Schematic of horizontal sections through the cerebral cortex of a normal human brain compared to those of patients with cortical malformation: microcephaly, lissencephaly type I, polymicrogyria, subcortical band heterotopia (double cortex), and periventricular nodular heterotopia. The table summarizes the phenotypic manifestations associated with each malformation regarding brain size, cortical folding, and the formation of ectopias. The most representative effects are highlighted and color‐coded: Features negatively affected by the pathology are in red, features augmented in green, and particularities are in blue. Uncolored cells indicate additional alterations that may be associated with the primary defect.
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