Some of these molecules may be expressed as opposing gradients or in a region-specific manner before and/or independently, since dilation of input does not prevent formation of at least some basic region-specific cytoarchitectonic

features (Figure 1C; Arimatsu et al., 1992, Cohen-Tannoudji et al., RG7204 1994, Grove and Fukuchi-Shimogori, 2003, Miyashita-Lin et al., 1999, O’Leary and Borngasser, 2006, Rakic et al., 1991 and Rubenstein and Rakic, 1999). An instructive example of how new regions could emerge via differential expansion of the cortical surface is the demonstration that frontal cortex can be enlarged in surface area without change in the size of other areas via manipulation of the transcription factors Fgf8, Fgh17, and Emx2 (Cholfin and Rubenstein, 2008). Opposing molecular gradients during development can, at some points of their intersection, provide instructions and coordinates for the creation of the

new neocortical areas (Figure 1C). For example, prospective Broca and Wernicke areas, which are formed as islands in the frontal and temporal lobes display a distinct temporarily enriched gene expression pattern that is distinct from the mice or macaque cerebrum at the comparable prenatal stages (e.g. Abrahams et al., 2007, Johnson et al., 2009 and Pletikos et al., 2013; Figure 2). The complex process of radial glia-guided neuronal Volasertib purchase migration of projection neurons was probably introduced during evolution to enable translation of the protomap at the VZ to the overlying cerebral cortex and preservation of neuronal positional information (Rakic, (-)-p-Bromotetramisole Oxalate 1988). The cellular and molecular mechanisms underlying this complex event involve cooperation of multiple genes and molecules including astrotactin, doublecortin, glial growth factor, erbB, Reelin, Notch, NJPA1, Integrins, Sparc-like1, Ephs, MEKK4, various calcium channels, receptors, and many others (e.g., Anton et al., 1999, Gleeson and Walsh, 2000, Hatten, 2002, Gongidi et al., 2004, Hashimoto-Torii et al., 2008,

Hatten, 2002, Komuro and Rakic, 1998, Nadarajah and Parnavelas, 2002, Reiner et al., 1993, Sarkisian et al., 2006 and Torii et al., 2009). Radial migration is particularly elaborate in the convoluted primate cerebrum, requiring modification of the radial glia (Rakic, 2003). This process is extremely relevant to human cerebral function, as neuronal migrational abnormalities are a major cause of human neurodevelopmental conditions (Gleeson and Walsh, 2000 and Lewis and Levitt, 2002). Yet mutations that cause severe abnormalities in human brain may cause far more subtle phenotypes in mouse, consistent with the exigencies of much longer migration in humans (e.g., Gleeson and Walsh, 2000 and Lewis and Levitt, 2002). There are also several examples of new types of neurons in the human cerebrum, including von Economo neurons, which are also observed in the brains of other large mammals and yet still may play an important role in human cerebral cortex (Butti et al., 2013).