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in collagen IV, nidogen, perlecan and fibronectin (Akita et al. 2008 ; Fietz et al.
2012 ; Garcion et al. 2004 ; Lathia et al. 2007 ; Milošević et al. 2014 ). The exact role
of different ECM molecules has yet to be fully elucidated, but Tenascin-C seems to
control the NEP-to-RGC maturation process via orchestrating the activity of FGFs
and BMPs (Garcion et al. 2004 ; Theocharidis et al. 2014 ) and glycosaminoglycans
regulate proliferation (Sirko et al. 2010 ). Moreover, NSCs of the VZ bind to ECM
via integrins and syndecan and these interactions are crucial for their periventricular
positioning, for interkinetic nuclear migration and for regulating the angle of divi-
sion (Loulier et al. 2009 ; Marthiens and ffrench-Constant 2009 ). The latter is of key
importance in controlling the type of division, with symmetric divisions being
dependent on the split of a small fragment of the apical pole of the cell membrane
(Kosodo et al. 2004 ). The asymmetry of division of NSCs and the ensuing cell fate
are also affected by N-cadherin and β-catenin, components of the molecular machin-
ery of the adherens junctions that are formed between cells of the VZ (Draganova
et al. 2015 ; Jiang and Nardelli 2015 ; Marthiens and Ffrench-Constant 2009 ). The
existence of adherens junctions is important for the correct positioning of RGCs and
when impaired, for example by the genetic perturbation of afadin expression
-another of their components- it can lead to cortical malformations similar to human
pathologies such as lissencephaly and double cortex (Yamamoto et al. 2015 ).
Recently, a better image of how local extrinsic cues signal to NSCs via the ECM has
been elucidated in the developing chick cortex. Wnt7alpha signalling among neigh-
bouring cells was reported to be mediated through integrin/decorin (another ECM
component) interactions in order to control proliferation and differentiation (Long
et al. 2016 ). Finally, the location of NEP cells and RGCs around the neural tube/
ventricle, especially the observation that mitosis occurs only at the surface of the
ventricle (Fig. 6.1a), also suggests that factors from the CSF most probably act upon
NSCs. Indeed, factors such as Wnts, BMPs (Lehtinen et al. 2011 ), IGFs, FGFs and
Shh (that is sensed by the apically positioned single cilium of each NSC) regulate
proliferation and specification of progenitors (briefly reviewed in Jiang and Nardelli
( 2015 )). Lehtinen and colleagues (Lehtinen et al. 2011 ) reported expression of the
receptor of IGF1 and 2 at the apical membrane of NSCs and showed that NSCs lack
expression of these growth factors. They also confirmed that IGF1 and 2, produced
by the embryonic choroid plexus, are crucial in supporting proliferation of embry-
onic NSCs. In the spinal cord, where the succession of neurogenesis and oligoden-
drogenesis has been investigated extensively, Shh secreted at the ventral neural tube
instructs the generation of oligodendrocyte progenitors whilst BMPs from the dor-
sal domains instruct the generation of motor neurons (Mekki-Dauriac et al. 2002 ).
The bipolar morphology of NEP cells and especially of RGCs, allows them to act
as scaffolds for the guided migration of their daughter cells that move towards the
pial surface in order to occupy their correct position within the 6-layered cortex
(Rakic 2003 ). Therefore, RGCs remain in constant and direct contact with migrat-
ing progeny (Cameron and Rakic 1994 ), a process controlled by integrins (Anton
et al. 1999 ), although shifts between neighbouring RGC basal processes (tangential
migration) occur under the control of ephrin signalling (Torii et al. 2009 ).
Interestingly, at the end of neurogenesis, when the appropriate number of neurons
E. Andreopoulou et al.