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Deconstructing cortical folding: genetic, cellular and mechanical determinants

Nature Reviews Neuroscience volume 20, pages 161–176 (2019)Cite this article

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Abstract

Folding of the cerebral cortex is a fundamental milestone of mammalian brain evolution and is associated with dramatic increases in size and complexity. New animal models, genetic tools and bioengineering materials have moved the study of cortical folding from simple phenomenological observation to sophisticated experimental testing. Here, we provide an overview of how genetics, cell biology and biomechanics shape this complex and multifaceted process and affect each other. We discuss the evolution of cortical folding and the genomic changes in the primate lineage that seem to be responsible for the advent of larger brains and cortical folding. Emerging technologies now provide unprecedented tools to analyse and manipulate cortical folding, with the promise of elucidating the mechanisms underlying the stereotyped folding of the cerebral cortex in its full complexity.

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Fig. 1: Anatomy and mechanics of cortical folding: push, not pull.
Fig. 2: Cellular mechanisms of cortical growth and folding: progenitor cells.
Fig. 3: Genetic regulation of cortical folding: progenitor cells and neuronal migration.
Fig. 4: Genetic patterning of cortical folds.
Fig. 5: Genetic evolution and cortical folding.
Fig. 6: Three key players in cortical folding: gene expression, cellular mechanisms and mechanical forces.

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Acknowledgements

The authors thank members of the Borrell laboratory, P. Bayly, R. Toro, M. Götz and W. Huttner, for insightful discussions. The authors apologize to colleagues whose research was not cited owing to the broad scope and space limitations of this Review. The authors’ research was supported by a European Research Grant (CORTEXFOLDING-309633), a Spanish Ministry of Economy and Competitiveness Grant (SAF2015-69168-R), the European Union Seventh Framework Programme (FP7/2007-2013, under the project DESIRE-602531) and the Spanish State Research Agency through the ‘Severo Ochoa’ Programme for Centers of Excellence in Research and Development (reference SEV-2017-0723).

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Nature Reviews Neuroscience thanks H. Kawasaki and the other anonymous reviewer(s) for their contribution to the peer review of this work.

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  1. Instituto de Neurociencias, Agencia Estatal Consejo Superior de Investigaciones Científicas and Universidad Miguel Hernández, San Juan de Alicante, Spain

    Cristina Llinares-Benadero & Víctor Borrell

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  1. Cristina Llinares-Benadero
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C.L.-B. and V.B. researched data for the article, contributed substantially to the discussion of content, wrote the article and reviewed and edited the manuscript before submission.

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Correspondence to Víctor Borrell.

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Glossary

Gyri

Also known as ‘folds’ or ‘convolutions’. Rounded elevations of cortical tissue between two sulci that contain all six neuronal layers bending outwards, such that the deep layers on either side of a gyrus come close together.

Sulci

Also known as ‘fissures’. Depressions or grooves of cortical tissue that contain all six neuronal layers bending inwards, such that the superficial cortical layers come close together on either side of a sulcus.

Gyrencephalic

The characteristic of a brain presenting cortical folds, giving a convoluted or wrinkled appearance.

Gyral crown

Also known as the ‘gyral crest’. The top or outermost part of a gyrus.

Sulcal fundus

Also known as the ‘sulcal pit’. The bottom or deepest part of a sulcus.

Lateral walls

Portions of cortex between gyral crowns and sulcal fundi.

Cellular ectopias

Also known as ‘cellular heterotopias’. Cells positioned in an abnormal location.

Hydraulic pressure

Force exerted by a fluid onto the surrounding tissue that contains it under pressure.

Cranial sutures

Fibrous joints between the cranial bones.

Modulus

Measure of a mechanical property of a material. The elastic modulus is the measure of the resistance of an object to being deformed elastically after stress is applied.

Stiffness

Property of a material that defines its resistance to being deformed after force is applied to it.

Cortical plate

(CP). Transient layer of the developing cortex, located beneath the marginal zone and containing the neurons that most recently finished radial migration.

Viscoelastic instability

Property of nearly inertia-less, non-Newtonian, flowing, complex fluids, such as polymer melts and solutions.

Anisotropy

The characteristic of materials of having different physical or mechanical properties when measured along different axes.

Delamination

Detachment from the apical adherens junction belt, followed by basal movement, away from the ventricular zone.

Lissencephaly

The characteristic of a brain without cortical folds, smooth or unfissured.

Intermediate progenitor cells

(IPCs). Germinal cells born from apical radial glial cells that populate the subventricular zone (basal from the ventricular zone) and produce neurons.

Gastrulation

Phase of early embryonic development during which the single-layered blastula is reorganized into a multilayered gastrula.

Hot spots

Regions in the genome that exhibit elevated rates of a specific event. In evolutionary hot spots, the local sequence of DNA has changed rapidly during evolution.

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Llinares-Benadero, C., Borrell, V. Deconstructing cortical folding: genetic, cellular and mechanical determinants. Nat Rev Neurosci 20, 161–176 (2019). https://doi.org/10.1038/s41583-018-0112-2

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