87has been produced, RGCs receive feedback instructing them to switch towards glio-
genesis; cardiotrophin-1 produced by neurons has been reported to be one such
signal (Barnabé-Heider et al. 2005 ).
The third compartment of each RGC, which shows functionally distinct interac-
tions with the microenvironment, is the endfoot of the basal process at the pial sur-
face. The pial surface is an area of the developing nervous system that is especially
rich in ECM molecules, characterized by the expression of components such as
nidogen, collagen IV and perlecan that are excluded from the main embryonic corti-
cal tissue (Fietz et al. 2012 ; Lathia et al. 2007 ). The multiple interactions between
integrins expressed by RGCs and different laminins of the basement membrane of
the pial/meningeal surface are of paramount importance for the correct migration
and positioning of newborn neurons. Defects in these interactions lead to patholo-
gies reminiscent of cobblestone lissencephaly and double cortex in humans
(Belvindrah et al. 2007a; Graus-Porta et al. 2001 ; Yamamoto et al. 2015 ). Notably,
the laminin- integrin interactions seem to be dispensable for the correct proliferative
behaviour of RGCs (Haubst et al. 2006 ), but very instrumental for their survival
(Radakovits et al. 2009 ).
6.2.2 Evolution
During evolution, this prototype architecture of the embryonic cortex changed with
the appearance of additional types of neural progenitors within the VZ, but most
importantly with the emergence of novel stem and progenitor populations located in
novel germinal zones (reviewed in Borrell and Calegari ( 2014 )). In mammals,
RGCs started dividing asymmetrically in order to generate intermediate (or basal)
progenitors that migrate deeper into the tissue forming the Sub-Ventricular Zone
(SVZ). These progenitors undergo a number of mitoses before terminally differen-
tiating and their emergence allowed the formation of the 6-layered neocortex
(Wilsch-Bräuninger et al. 2016 ). In a next evolutionary step, a third group of pro-
genitors located even deeper in the tissue (outer SVZ/oSVZ) appeared in lissenece-
phalic species (such as rodents) but their population became much more prominent
in primates. oSVZ cells generate larger clones than intermediate progenitors (Pollen
et al. 2015 ) and their presence is correlated with the explosive expansion of neocor-
tex accommodated by the formation of gyrencephalia (Wilsch-Bräuninger et al.
2016 ). In rodents, the transcriptome of the SVZ (of intermediate progenitors) is
similar to that found at the cortical plate where newborn neurons mature (Fietz et al.
2012 ) and significantly distinct to that of the VZ. This, applies also to ECM compo-
nents. In contrast, in the human developing cortex the ECM signature of all three
progenitor pools seems to be similar, but significantly different from that of the
cortical plate (Fietz et al. 2012 ). This might reflect size requirements as the human
brain has scaled in a way that allowed for larger extracellular space (Herculano-
Houzel 2012 ; Syková and Nicholson 2008 ). For example, the ECM molecule
Tenascin-C, that in the mouse participates in the creation of the VZ environment but
6 Being a Neural Stem Cell: A Matter of Character But Defined...