Growth and folding of the mammalian cerebral cortex: from molecules to malformations

Key Points 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 the extent of gyrification of the cerebral cortex both influence brain function in mammals. In this Review, Sun and Hevner examine the mechanisms underlying cortical growth and folding, and discuss how dysfunction in these processes leads to cortical malformations. 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.