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Review
. 2023 Dec 18;58(24):2836-2849.
doi: 10.1016/j.devcel.2023.11.004.

Shaping the brain: The emergence of cortical structure and folding

Shyam K Akula  1 , David Exposito-Alonso  1 , Christopher A Walsh  2
Affiliations
Review

Shaping the brain: The emergence of cortical structure and folding

Shyam K Akula et al. Dev Cell. .

Abstract

The cerebral cortex-the brain's covering and largest region-has increased in size and complexity in humans and supports higher cognitive functions such as language and abstract thinking. There is a growing understanding of the human cerebral cortex, including the diversity and number of cell types that it contains, as well as of the developmental mechanisms that shape cortical structure and organization. In this review, we discuss recent progress in our understanding of molecular and cellular processes, as well as mechanical forces, that regulate the folding of the cerebral cortex. Advances in human genetics, coupled with experimental modeling in gyrencephalic species, have provided insights into the central role of cortical progenitors in the gyrification and evolutionary expansion of the cerebral cortex. These studies are essential for understanding the emergence of structural and functional organization during cortical development and the pathogenesis of neurodevelopmental disorders associated with cortical malformations.

Keywords: Sonic Hedgehog; cortical folding; ferret models; gyration; neuronal migration; outer radial glia; polymicrogyria.

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Conflict of interest statement

Declaration of interests The authors declare no competing interests.

Figures

Figure 1.
Figure 1.. Temporal stages and progenitor types in the human developing neocortex.
During early human brain development, a layer of neuroepithelial cells (NECs), spanning from the ventricular surface to the pial surface, populates the developing neural tube and undergoes self-renewing divisions to generate more NECs (symmetric divisions) in early developmental stages. They then elongate and differentiate into radial glial cells (RGCs), which also undergo symmetric divisions to expand the population of progenitors. During the neurogenic period, RGCs begin to divide asymmetrically to generate neurons while self-maintaining the progenitor pool, either generating neurons directly or producing neurons indirectly through intermediate progenitor cells (IPCs). Apical radial glial cells (aRGCs) are defined by residing in the ventricular zone (VZ) and by establishing contacts at both the apical and basal surfaces of the developing cortex. Later in development, aRGCs can also give rise to basal radial glial cells (bRGCs) by delamination of the apical belt of adherens junctions attached to the ventricular surface and translocation of their somas to the subventricular zone (SVZ). Based on marker expression, bRGCs have multiple subtypes, including HOPX+ bRGCs. Migrating neurons generated by aRGCs or bRGCs use the RG scaffold of both types of progenitors to migrate through the intermediate zone (IZ) into the developing cortical plate (CP), which contributes to the growth of the CP. By the second trimester of pregnancy (gestational week 17), aRGCs transform into truncated RGCs with their basal process terminating in the border between the inner and outer layers of the SVZ (iSVZ/oSVZ); thus, the RG scaffold becomes truncated at the iSVZ/oSVZ border. Cortical neurons are born in an inside-out fashion, with neurons destined to deeper layers (L6) born first and neurons destined to superficial layers (L2) born last. Density plots shown on the bottom represent the different neurogenic stages that preferentially generate neurons committed to each cortical layer. The extended neurogenic period for superficial layer neurons (L2–3), coincides with the expansion of bRGC proliferation and is considered a hallmark of human brain evolution.
Figure 2.
Figure 2.. Cellular and molecular mechanisms of radial glial cells promote cortical folding.
(A) The current model of cortical folding proposes a key role for basal radial glial cells (bRGCs), which are characterized by a highly proliferative capacity and are especially abundant in the outer subventricular zone (oSVZ). Regional differences in neurogenesis are found across the developing cortical mantle in gyrencephalic species (especially noticeable in the oSVZ): regions destined to prospective gyrus (proto-gyri) have greater densities of diving progenitor cells than regions destined to prospective sulci (proto-sulci) ,. Consistently, a subclass of bRGCs labeled by the marker HOPX in the developing ferret cortex is found in greater densities in proto-gyri . The differential density of basal progenitors results in differential production and accumulation of neurons in the developing cortical plate (CP), which causes a greater degree of tangential expansion (horizontal double arrow) in proto-gyri relative to proto-sulci. Moreover, there is a progressive divergence in the trajectory of radial glial (RG) fibers during gyrus formation due to the highly proliferative population of bRGCs that intercalate their fibers with preexisting ones . This fanned array of RG fibers in prospective gyral regions contributes to the tangential spread of migrating neurons guided by this scaffolding. In contrast, radial glial fibers typically show parallel trajectories in proto-sulci, which likely limits the tangential spread of migrating neurons. (B) Schematic illustrating the effects of Sonic Hedgehog (Shh) signaling in cortical folding. HOPX+ bRGCs were shown to respond to activation and inhibition of Shh signaling activity in inverse ways: Shh stimulation (with the amino-terminal fragment of Shh, Shh-N) results in increased densities of HOPX+ bRGCs, whereas Shh suppression (with the competitive inhibitor HhipΔ22) results in a reduced population of HOPX+ bRGCs . These effects lead to bidirectional changes in cortical folding: Shh stimulation results in larger gyri, whereas Shh inhibition leads to smaller gyri .
Figure 3.
Figure 3.. Evolutionary expansion of the human neocortex and cortical progenitors.
(A) A hallmark of human neocortical evolution is the expansion of superficial layer neurons. Left, image of a coronal section of the human neocortex illustrating the relative thickness of cortical layers (L1-L6). Red shade highlights the expansion of superficial layers, especially L2–3, in the human neocortex. Image adapted from Allen Institute for Brain Science. Image credit: Allen Institute for Brain Science: https://human.brain-map.org/ish/specimen/show/79946224 (specifically, Nissl-stained brain section from the right-hand side panel: Image 7 of 8). Right, drawing illustrating the expanded neuronal diversity found in superficial layers of the human neocortex [as described in ]; labels indicate the marker genes of specific types of excitatory pyramidal cells. (B) Gene duplications in evolution that regulate the behavior of cortical progenitors. ARHGAP11B arose 5 million years ago by partial duplication of ARHGAP11A. Three human-specific paralogs (NOTCH2NLA, NOTCH2NLB, and NOTCH2NLC) derived from duplication of NOTCH2. CROCCP2 arose through partial duplication of exons 13–21 of CROCC in the Hominini lineage (chimpanzees and humans). TBC1D3 arose in the Hominoid lineage (great apes) from a segmental duplication, with multiple copies found in the human genome and only a single copy found in the chimpanzee genome. TMEM14B arose in the primate lineage, including Old World and New World monkeys and apes. In parallel, experimental manipulations in mice, ferrets, and marmosets, as well as cerebral cortical organoids, have revealed a role for these genes in inducing cortical folding induction and/or cortical size expansion. Symbols represent the animal models in which cortical folding appeared as a result of overexpression experiments. (C) Distinctive features of cortical progenitors during human brain development. The schema compiles 5 cellular features reviewed in this work: extracellular matrix components, responsiveness to extracellular signaling cues, regulation of fatty acid synthesis, mitochondrial dynamics and metabolism, and ciliary dynamics and trafficking.
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