%A Lewitus,Eric %A Kelava,Iva %A Huttner,Wieland B %D 2013 %J Frontiers in Human Neuroscience %C %F %G English %K Neocortex,gyrencephaly,Subventricular zone,neural progenitors,Mammals,Extracellular Matrix,phylogenetics %Q %R 10.3389/fnhum.2013.00424 %W %L %M %P %7 %8 2013-August-01 %9 Hypothesis and Theory %+ Prof Wieland B Huttner,Max Planck Institute of Molecular Cell Biology and Genetics,Pfotenhauerstr. 108,Dresden,01099,Germany,huttner@mpi-cbg.de %# %! The conical migration of neurons drives neocortical folding %* %< %T Conical expansion of the outer subventricular zone and the role of neocortical folding in evolution and development %U https://www.frontiersin.org/articles/10.3389/fnhum.2013.00424 %V 7 %0 JOURNAL ARTICLE %@ 1662-5161 %X There is a basic rule to mammalian neocortical expansion: as it expands, so does it fold. The degree to which it folds, however, cannot strictly be attributed to its expansion. Across species, cortical volume does not keep pace with cortical surface area, but rather folds appear more rapidly than expected. As a result, larger brains quickly become disproportionately more convoluted than smaller brains. Both the absence (lissencephaly) and presence (gyrencephaly) of cortical folds is observed in all mammalian orders and, while there is likely some phylogenetic signature to the evolutionary appearance of gyri and sulci, there are undoubtedly universal trends to the acquisition of folds in an expanding neocortex. Whether these trends are governed by conical expansion of neocortical germinal zones, the distribution of cortical connectivity, or a combination of growth- and connectivity-driven forces remains an open question. But the importance of cortical folding for evolution of the uniquely mammalian neocortex, as well as for the incidence of neuropathologies in humans, is undisputed. In this hypothesis and theory article, we will summarize the development of cortical folds in the neocortex, consider the relative influence of growth- vs. connectivity-driven forces for the acquisition of cortical folds between and within species, assess the genetic, cell-biological, and mechanistic implications for neocortical expansion, and discuss the significance of these implications for human evolution, development, and disease. We will argue that evolutionary increases in the density of neuron production, achieved via maintenance of a basal proliferative niche in the neocortical germinal zones, drive the conical migration of neurons toward the cortical surface and ultimately lead to the establishment of cortical folds in large-brained mammal species.