An important feature of cerebral cortex development is the increase in the thickness and folding of surface areas in many species.
Abnormal cortical development that affects growth and folding causes brain malformations such as microcephaly and lissencephaly.
Cortical neural progenitors can be characterized into four subtypes according to their apical and basal positions in the ventricular zone and subventricular zone: apical radial glial cells, apical intermediate progenitors, basal radial glial cells and basal intermediate progenitors.
Cell cycle progression, apoptosis, cilia and microRNAs control distinct aspects of cortical neural progenitor expansion and cortical size.
Many microcephaly-associated genes are involved in centrosome function and in turn control symmetrical versus asymmetrical divisions of cortical neural progenitors and cortical size.
Gyrencephaly — that is, anatomical folding of the neocortex to form gyri and sulci — seems to be a trait that arose in the ancestor of all mammals.
Cortical neural progenitors at basal positions in the ventricular zone and subventricular zone play a substantial part in expanding cortical surface areas and folding.
Many factors, such as afferent fibres and axonal interactions, ventricular surface expansion, pial invagination and meningeal signalling, contribute to development of gyri in the cortex.
The size and extent of folding of the mammalian cerebral cortex are important factors that influence a species' cognitive abilities and sensorimotor skills. Studies in various animal models and in humans have provided insight into the mechanisms that regulate cortical growth and folding. Both protein-coding genes and microRNAs control cortical size, and recent progress in characterizing basal progenitor cells and the genes that regulate their proliferation has contributed to our understanding of cortical folding. Neurological disorders linked to disruptions in cortical growth and folding have been associated with novel neurogenetic mechanisms and aberrant signalling pathways, and these findings have changed concepts of brain evolution and may lead to new medical treatments for certain disorders.
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The authors thank J. Knauss for critical reading of the manuscript. The authors thank W. Dobyns at Seattle Children's Hospital, Washington, USA, for sharing the unpublished images used in Box 1. This work was supported by the Hirschl/Weill-Caulier Trust (T.S.), R01-MH083680 (T.S.), R21-MH087070 (R.F.H.) and R01-NS085081 (R.F.H.) grants from the US National Institutes of Health.
The authors declare no competing financial interests.
- SUN-domain-containing protein
A protein containing SUN (Sad1p and UNC-84) domains in the carboxy-terminal regions. These proteins are often involved in positioning of the nucleus in a cell.
- Joubert syndrome
A genetic disorder that affects the cerebellum. The most common features include ataxia and abnormal eye and tongue movements. Abnormal functions of cilia are associated with this disorder.
A cell structure that is composed mainly of tubulin. A centrosome is made up by a pair of centrioles. Centrioles are involved in the organization of the mitotic spindle in dividing cells.
A medical condition in which there is an abnormal accumulation of cerebrospinal fluid in the ventricles or cavities of the brain.
An RNAase III enzyme that cleaves double-stranded RNA and microRNA precursors into short (20–25 base pairs) double-stranded RNA fragments. It facilitates the formation of the RNA-induced silencing complex (RISC) and participates in the RNAi pathway and microRNA-mediated gene silencing.
The laminar and radial arrangement of myelinated fibres in cortical areas. Like cytoarchitecture (the organization of cells), myeloarchitecture reveals important structural features of cortical areas.
- Monosomy 1p36
A chromosomal deletion syndrome, in which the distal tip of the short arm of chromosome 1 (containing dozens of genes) is deleted. The syndrome is associated with neurological problems, such as epilepsy, and cortical malformations, including polymicrogyria.
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Sun, T., Hevner, R. Growth and folding of the mammalian cerebral cortex: from molecules to malformations. Nat Rev Neurosci 15, 217–232 (2014). https://doi.org/10.1038/nrn3707
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