Crianza

In the 17th century, Thomas Willis first proposed that higher cognitive functions originate from the sheer size of the brain (Molnár, 2011). The increase of intellectual capacity during mammalian evolution is believed to highly correlate with the increase in brain size. In this context, the cerebral cortex has undergone an impressive expansion including profound gyrification to accommodate an enormous increase in neuron numbers (Kriegstein et al., 2006; Rakic, 2009; Cheung et al., 2010; Lui et al., 2011; Borrell and Reillo, 2012). In 1664 Willis already realized, that the gyrifications of the human cerebral cortex are larger and more numerous as compared to other species (Willis, 1664).

The evolutionary increase in cortical size correlates with the appearance of the so-called outer subventricular zone in larger brains. Hereby, the subventricular zone is divided into inner (iSVZ) and outer (oSVZ) areas separated by a layer of fibers. The strong expansion of larger brains is believed to be due to an increase in the number of basal progenitors, which subsequently increase the number of neurons. In this context, the strong proliferation of cells residing in the SVZ of primates correlates with the main wave of corticogenesis (Rakic, 1974; Lukaszewicz et al., 2005; Lui et al., 2011). Basal progenitors have been suggested to be the main source of cortical expansion. Indeed, genetic studies in humans showed that the cause of congenital microcephaly was silencing of the transcription factor TBR2 (EOMES) (Baala et al., 2007), a protein shown to be functionally required for SVZ neurogenesis (Arnold et al., 2008; Sessa et al., 2008; 2010) and also used as a marker for basal progenitors (Bulfone et al., 1999; Faedo et al., 2002; Englund, 2005).

Recently, another type of progenitors has been described and implicated in cortical expansion and folding (see also 2.1.1). This type of cell shares several characteristics such

as Pax6 expression with radial glial cells, but in contrast to those has only a basal process lacking the apical contact to the ventricular surface and their cell body resides in the oSVZ. This cell type is called outer radial glial cell (oRG) or basal radial glial cell (bRG). Outer radial glial cells contribute to cortical expansion by representing another type of proliferating progenitor (Fietz et al., 2010; Hansen et al., 2010; Reillo and Borrell, 2011; Reillo et al., 2011; Shitamukai et al., 2011; Wang et al., 2011; Kelava et al., 2012). Expanding the population of radial glia in a distinct germinal zone is a mechanism for increased neuron production that is highly relevant for building a larger brain (Lui et al., 2011). Despite their role in proliferation and expansion of neuron numbers, oRGs are also a crucial part of the migratory scaffold in the developing brain. As expanded, folded brains have a strong increase in basal surface with only slightly increased ventricular surface oRGs are needed to keep the fiber density constant throughout the process of radial expansion (Lui et al., 2011; Reillo and Borrell, 2011; Reillo et al., 2011; Martínez-Cerdeño et al., 2012) (see Figure 4). This interpretation is strongly supported by the appearance of larger numbers of oRGs in brains with a high degree of gyrification (Fietz and Huttner, 2010; Borrell and Reillo, 2012; Martínez-Cerdeño et al., 2012). In contrast, the little and lissencephalic mouse brain has only small numbers of oRGs (Shitamukai et al., 2011; Wang et al., 2011). In human cortical development the number of neurons in the cortical plate increases by about 5 billion new neurons between the 13th and the 20th gestation week. In this context it has been suggested, that on average there must be 1000 neurons arriving every second in the CP during that period indicating that there may be 500-1000 progenitors dividing every second to produce this enormous output (Martínez-Cerdeño et al., 2012). Therefore, tight control of neuronal production and guidance through RGs, BPs and oRGs is crucial for proper brain development.

Figure 4: Differences in neocortical development of the rodent and human brain

(A) Model of the current view of rodent corticogenesis. Radial glia (RG) mostly generate intermediate progenitors (IP also called basal progenitors (BP)) that divide again to produce neurons. Newborn neurons migrate along RG fibers towards the cortical plate. Small numbers of outer radial glial cells (oRG) exist in the murine brain. (B) Simplified Model of the human developing neocortex. The increase of the subventricular zone (SVZ) divided into inner- and outer SVZ is illustrated. The number of radial fibers that neurons can use to migrate along is increased due to the abundance of oRGs. Additionally, the number of ontogenetic “units” is significantly increased through the addition of oRG cells to ventricular radial glial cells (vRG). Integrin and Notch signaling are involved in maintenance of oRGs. Additionally, short neuron precursors (SNPs) are depicted in (A) and (B). Transcription factor combinations expressed by the different progenitor types is indicated. Illustration from Lui et al (2011)

In summary, a diversity of progenitors exists in the developing cerebral cortex. Amongst them neuroepithelial cells (that mainly self replicate to initially increase the pool of stem cells), RG cells, SNPs, BPs and oRGs. All of them contribute to the formation and expansion of the cerebral cortex. A general concept of forebrain development indicates that the progenitor pool initially needs to be expanded leading to a tangential expansion at first place. In order to incorporate a large number of neurons, radial expansion takes place later eventually leading to cortical folding and gyrification in higher species (Smart and McSherry, 1986a; 1986b; Rakic, 2009; Lui et al., 2011; Molnár, 2011; Borrell and Reillo, 2012).