Figure 2. Cellular and molecular mechanisms of radial glial cells promote cortical folding.
(A) The current model of cortical folding proposes a key role for basal radial glial cells (bRGCs), which are characterized by a highly proliferative capacity and are especially abundant in the outer subventricular zone (oSVZ). Regional differences in neurogenesis are found across the developing cortical mantle in gyrencephalic species (especially noticeable in the oSVZ): regions destined to prospective gyrus (proto-gyri) have greater densities of diving progenitor cells than regions destined to prospective sulci (proto-sulci) 40,80. Consistently, a subclass of bRGCs labeled by the marker HOPX in the developing ferret cortex is found in greater densities in proto-gyri 31. The differential density of basal progenitors results in differential production and accumulation of neurons in the developing cortical plate (CP), which causes a greater degree of tangential expansion (horizontal double arrow) in proto-gyri relative to proto-sulci. Moreover, there is a progressive divergence in the trajectory of radial glial (RG) fibers during gyrus formation due to the highly proliferative population of bRGCs that intercalate their fibers with preexisting ones 40. This fanned array of RG fibers in prospective gyral regions contributes to the tangential spread of migrating neurons guided by this scaffolding. In contrast, radial glial fibers typically show parallel trajectories in proto-sulci, which likely limits the tangential spread of migrating neurons. (B) Schematic illustrating the effects of Sonic Hedgehog (Shh) signaling in cortical folding. HOPX+ bRGCs were shown to respond to activation and inhibition of Shh signaling activity in inverse ways: Shh stimulation (with the amino-terminal fragment of Shh, Shh-N) results in increased densities of HOPX+ bRGCs, whereas Shh suppression (with the competitive inhibitor HhipΔ22) results in a reduced population of HOPX+ bRGCs 31. These effects lead to bidirectional changes in cortical folding: Shh stimulation results in larger gyri, whereas Shh inhibition leads to smaller gyri 31.