Regulation of Cerebral Cortex Folding by Controlling Neuronal Migration via FLRT Adhesion Molecules

Abstract

The folding of the mammalian cerebral cortex into sulci and gyri is thought to be favored by the amplification of basal progenitor cells and their tangential migration. Here, we provide a molecular mechanism for the role of migration in this process by showing that changes in intercellular adhesion of migrating cortical neurons result in cortical folding. Mice with deletions of FLRT1 and FLRT3 adhesion molecules develop macroscopic sulci with preserved layered organization and radial glial morphology. Cortex folding in these mutants does not require progenitor cell amplification but is dependent on changes in neuron migration. Analyses and simulations suggest that sulcus formation in the absence of FLRT1/3 results from reduced intercellular adhesion, increased neuron migration, and clustering in the cortical plate. Notably, FLRT1/3 expression is low in the human cortex and in future sulcus areas of ferrets, suggesting that intercellular adhesion is a key regulator of cortical folding across species.

Lkb1 regulates granule cell migration and cortical folding of the cerebellar cortex

“…In the gyrencephalic neocortex of humans and some mammals, cortical folding has been attributed to outer radial glial (oRG), a population of radial glia that are largely absent in mice and other smooth-brained (lissencephalic) species 60 . Interestingly, recent studies in mice suggest that cortex folding does not require progenitor cell proliferation but is associated with clustering of neurons along the tangential axis due to defective cell migration 61 .…”

Unfolding the Folding Problem of the Cerebral Cortex: Movin’ and Groovin’

“…Beyond the specific results of this elegant paper, the new range of potential intercellular differential adhesion and interaction mechanisms unveiled by del Toro et al (2017) will be deeply influential, and this work is likely to become a landmark study toward understanding how gyrencephalic brain structure is physically built during development. One future step might be to ask whether the findings in this study are generalizable and applicable across different types of folding in brains– more widely in the cerebellum, e.g., or at recognizable folds and flexures.…”

“…In a recent paper in Cell, del Toro et al (2017) show that changing the adhesive properties of neurons in the normally lissencephalic mouse cortex leads to the formation of stereotyped folding. …”

“…Aristotle, who saw function in structure, canonized gyrification as the most prominent of brain features when he postulated that the brain, due to its convoluted vascularized surface, functioned as a type of radiator, a cooling unit for the vital heat pumped by the heart (Gross, 1995). The quest to explain this striking folding of the brain has been enchanting scientists ever since, and work published this month in Cell by del Toro, Klein, and colleagues uncovers an exciting new twist to this convoluted phenomenon (del Toro et al, 2017). …”

“…Directionality and variable rates of migration, linked to biophysical folding mechanisms, are an attractive set of factors for sculpting the three-dimensional organization of an evolutionarily expanding cerebral cortex. It is this set of linked mechanisms that are investigated by del Toro, et al (del Toro et al, 2017). …”