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Why the cerebral cortex folds in some mammals but not in others has long fascinated and mystified neurobiologists. Over the past century—especially the past decade—researchers have used theory and experiment to support different folding mechanisms such as tissue buckling from mechanical stress, axon tethering, localized proliferation, and external constraints. In this review, we synthesize these mechanisms into a unifying framework and introduce a hitherto unappreciated mechanism, the radial intercalation of new neurons at the top of the cortical plate, as a likely proximate force for tangential expansion that then leads to cortical folding. The interplay between radial intercalation and various biasing factors, such as local variations in proliferation rate and connectivity, can explain the formation of both random and stereotypically positioned folds.
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Download Supplemental Figures 1-7 as a single PDF, or see below.
Supplemental Figure 1: Cortical folding in transgenic mice. Mice engineered to express a constitutively active form of beta-catenin in the telencephalon exhibit abnormally prolonged cortical precursor proliferation. Compared to wild-type mice, these transgenic mice have an enlarged skull, an enlarged brain, and a folded cerebral cortex. Note that the ventricular surface extends into the gyri. Adapted from Chenn & Walsh, 2002.
Supplemental Figure 2: Wrinkling of a layered hydrogel. Disk-shaped hydrogels were constructed to have a non-swelling core surrounded by a shell that swells when immersed in water. Shown at the top is the experimental set-up that allows researchers to observe changes in the hydrogel’s shape. The images at the bottom reveal how the shell buckles when the core is relatively elastic (A-D) and how it creases when the core is stiffer than the shell (E-H). In both cases, the system ultimately breaks (D and H). Reprinted with permission from Dervaux et al., 2011; copyright 2011 by the American Physical Society, http://journals.aps.org/prl/.
Supplemental Figure 3: Reducing intraventricular pressure causes folding of the cerebral wall. Desmond & Jacobson (1977) inserted a solid glass rod (top) or a hollow micropipette (bottom) into the cerebral ventricles of young chick embryos. Twenty-four hours later the intubated brains exhibited numerous folds of the cerebral wall; sham intubation had no such effect. Adapted from Desmond & Jacobson, 1977.
Supplemental Figure 4: The telencephalic vesicle in human embryos. As shown in these sagittal (left) and coronal (right) sections, the telencephalic vesicle in humans expands enormously between 7.5 and 9 weeks of gestation. During this ballooning stage, the telencephalic wall remains relatively thin (except for the subcortical ganglionic eminences) and smooth. The choroid plexus, which is critical for producing cerebrospinal fluid, expands in concert with the telencephalic vesicle. The cortical plate (blue) emerges around 9 weeks of gestation, but it is still thin in most places. Adapted from Bayer & Altman, 2008.
Supplemental Figure 5: Terminal translocation of the cell body into the outer cortical plate. (A) The cerebral cortex of mice thickens substantially between embryonic day 15.5 and postnatal day 3.5, but the outer cortical plate (a.k.a. primitive cortical zone) remains relatively constant in thickness. Its neurons are very young and do not yet express the mature neuronal marker Neu-N. (B) Time-lapse imaging reveals that young, radially migrating GFP-labeled neurons extend a leading process toward the brain surface. When this process reaches the marginal zone, the neuron rapidly pulls (translocates) its cell body into the outer cortical plate. Adapted from Sekine et al., 2011, with the author’s permission.
Supplemental Figure 6: Lengthening migration distance to the lateral cortex. Rat embryos were given a pulse of tritiated thymidine on embryonic day 17 (ED17) and sacrificed on ED18, 19, or 20. Heavily radioactive cells, which must have been born on day 17, are depicted in red. The data show that cells born on ED17 take only 2 days to reach dorsomedial neocortex, 3 days to reach dorsolateral cortex, and >3 days to reach ventral insular and olfactory cortex. They migrate to the latter destinations in the lateral cortical stream, which lengthens progressively as the corticostriatal junction moves dorsomedially. Adapted from Bayer et al., 1991.
Supplemental Figure 7: Cetacean versus human cerebral cortex. Dolphin and human brains are similar in size (~1,500 g), but the dolphin’s cortex is significantly thinner and more highly folded. Reproduced with permission from http://www.brains.rad.msu.edu, and http://brainmuseum.org, supported by the US National Science Foundation.