What disorders of cortical development tell us about the cortex: one plus one does not always make two

Abstract

The unique size and complexity of the human cerebral cortex are achieved via a long and precisely regulated developmental process controlling neurogenesis, neuronal migration and differentiation. Traditionally, disorders of cortical development have been classified on the basis of the most obvious defects in one of these developmental steps. However, the more we learn about the cellular biological roles of genes that are essential for cortical development, the more we realize that these functions map onto molecular processes, but not so cleanly onto anatomical processes. Essential genes might be involved in both proliferation and migration as well as differentiation, reflecting roles for underlying molecular mechanisms in different phases of development and causing a stunning variety of cortical defects.

Figure 1. Examples of abnormal cortical development leading to malformations

A. Normal cortical development results from a balance of progenitor cell proliferation, neurogenesis and neuronal migration, leading to normal cortical lamination. Progenitor cells are in yellow and neurons are in blue, for simplicity only one of the cortical layers is shown here. Abbreviations: CP, cortical plate, VZ, ventricular zone. B. Centrosomal defects can lead to different malformations: microcephaly (i), where progenitor proliferation is reduced, sometimes due to the formation of abnormal mitotic spindles, and neurogenesis is anticipated; or lissencephaly (ii), where a thickened, disorganized cortical plate is generated following migration defects, reduced cell motility, disrupted leading process formation, uncoupling of the centrosome and nucleus during nucleokinesis. C. Disruptions in the orientation of the radial glial scaffold, such as observed in cobblestone lissencephaly and some forms of polymicrogyria, lead to cortical dysplasia and neuronal overmigration through the basal lamina on the pial surface.