From genes to folds: a review of cortical gyrification theory

Abstract

Cortical gyrification is not a random process. Instead, the folds that develop are synonymous with the functional organization of the cortex, and form patterns that are remarkably consistent across individuals and even some species. How this happens is not well understood. Although many developmental features and evolutionary adaptations have been proposed as the primary cause of gyrencephaly, it is not evident that gyrification is reducible in this way. In recent years, we have greatly increased our understanding of the multiple factors that influence cortical folding, from the action of genes in health and disease to evolutionary adaptations that characterize distinctions between gyrencephalic and lissencephalic cortices. Nonetheless it is unclear how these factors which influence events at a small-scale synthesize to form the consistent and biologically meaningful large-scale features of sulci and gyri. In this article, we review the empirical evidence which suggests that gyrification is the product of a generalized mechanism, namely the differential expansion of the cortex. By considering the implications of this model, we demonstrate that it is possible to link the fundamental biological components of the cortex to its large-scale pattern-specific morphology and functional organization.

Fig. 1

Three distinct mechanisms proposed for gyrification. a The axonal tension hypothesis proposes that axons under tension pull regions of the cortex which are strongly connected together, causing folds. However, there are a number of problems with this hypothesis (1) axonal connectivity is not commensurate with the hypothesized pattern of connectivity; (2) axonal innervation post-dates the formation of folds; (3) axons are not under requisite tension to cause folding; (4) removal of axons during developing causes an increase in the number of folds. b The radial gradient hypothesis proposes that the increase in expansion of the supragranular layers relative to the infra-granular layers causes buckling. However several experimental observation militate against this (1) the incidence of bRG (which contribute to supragranular layer expansion) is similar in gyrencephalic and lissencephalic species; (2) gyrification may be induced without a change in the proliferation of bRG; (3) reduction in the proliferation of bRG does not change the degree of gyrification; (4) disruption in the formation of supragranular layer neurons does not affect gyrification. c The differential tangential expansion hypothesis proposes that tangential expansion of the cortex causes an increase in tangential pressure which is mitigated though buckling. Empirical evidence suggests that the pattern of differential expansion (predominantly influenced by the pattern of cytoarchitecture), causes pattern-specific folding. As such, the stability of folds represents the stability of expansion forces in that region

Fig. 2

Developmental neurogenesis is driven by apical radial glia (aRG) in the ventricular zone, and intermediate progenitor cells (IPCs) and basal radial glia (bRG) in the sub-ventricular zone