The Extracellular Matrix in the Evolution of Cortical Development and Folding

Abstract

The evolution of the mammalian cerebral cortex leading to humans involved a remarkable sophistication of developmental mechanisms. Specific adaptations of progenitor cell proliferation and neuronal migration mechanisms have been proposed to play major roles in this evolution of neocortical development. One of the central elements influencing neocortex development is the extracellular matrix (ECM). The ECM provides both a structural framework during tissue formation and to present signaling molecules to cells, which directly influences cell behavior and movement. Here we review recent advances in the understanding of the role of ECM molecules on progenitor cell proliferation and neuronal migration, and how these contribute to cerebral cortex expansion and folding. We discuss how transcriptomic studies in human, ferret and mouse identify components of ECM as being candidate key players in cortex expansion during development and evolution. Then we focus on recent functional studies showing that ECM components regulate cortical progenitor cell proliferation, neuron migration and the mechanical properties of the developing cortex. Finally, we discuss how these features differ between lissencephalic and gyrencephalic species, and how the molecular evolution of ECM components and their expression profiles may have been fundamental in the emergence and evolution of cortex folding across mammalian phylogeny.

Keywords: evolutionary conservation; extracellular matrix; folding; gene expression; microenvironment; radial glia.

FIGURE 1

Influence of extracellular matrix (ECM) on cortical progenitor cells. Schema summarizing the effects of ECM components on the proliferation and lineage of neuroepithelial cells (NEC), apical Radial Glia Cells (aRGC) and basal Progenitor Cells (bPC), including Intermediate Progenitor Cells (IPC) and basal RGCs (bRGC). Loss of Glypican 1, Syndecan-1, and Perlecan leads to a decrease in proliferation of NECs, while blocking β1 Integrin leads to apical detachment of aRGCs and loss of asymmetric divisions in the VZ. Knocking out Laminin α2, Laminin α4, and Retinoic acid secreted from the external meninges affects aRGC attachment to the basement membrane. Activation of Integrin αvß3 increases IPC proliferation and cell cycle re-entry, while Sox9 activation increases bPC proliferation via Laminin 211.

FIGURE 2

Role of extracellular matrix (ECM) on neuronal migration. Schema showing the role of ECM components on promoting the migration, termination of migration and maintenance of the basement membrane integrity in mouse developing cortex. Loss of Laminin γ1, Neuroglycan C, Syndecan 3, and overexpressing ECE2 leads to delay in migration, while loss of Laminin β1, Laminin IIIγ, Dystrophin or Reelin leads to overmigration of neurons and breaching of the basement membrane.