88
is not expressed in the SVZ parenchyma (Garcion et al. 2004 ), re-appears in the
human SVZ, both in the basal progenitor and the oSVZ compartments (Pollen et al.
2015 ). The necessity for NSCs to build and/or operate in microenvironments that
are specialized according to the future brain structure to be formed has been revealed
in another recent transcriptome analysis in the ferret (De Juan Romero et al. 2015 ).
When comparing NSC compartments between areas that give rise to folds or fis-
sures, the expression of genes correlated with cell-to-cell interactions, such as cad-
herin 8, and with the response to growth factors, such as FGF receptors 2 and 3, was
found to be significantly different (De Juan Romero et al. 2015 ).
6.2.3 Blood Vessels, Systemic Cues and Tissue Mechanics
As mentioned earlier, the CNS is a tissue constructed mostly by neural elements
(neurons and glia), with minimal contribution of other tissues, with the exception of
blood vessels (BVs). Although at the initial stages of neurogenesis (both in terms of
evolution and of development) NSCs become specified and proliferate in the
absence of vasculature, BVs become an important component of the NSC microen-
vironment (this has been reviewed in more detail in Koutsakis and Kazanis ( 2016 )).
Notably, although the levels of oxygenation of the embryonic CNS are not known
in detail, the culture of embryonic stem cell-derived NSCs in low oxygen (3%;
rather than in the usual 20% culture conditions), which is thought to be more rele-
vant to normal situation, is reported to enhance survival and differentiation effi-
ciency (Stacpoole et al. 2011 ). The processes of neurogenesis and angiogenesis are
considered to be “coupled” due to their co-ordination during the seasonal changes
in the size of certain nuclei in the brain of songbirds (Louissaint et al. 2002 ).
Furthermore, endothelial cells can enhance neurogenesis in co-culture assays
(Androutsellis-Theotokis et al. 2010 ; Shen 2004 ). However, the existence of more
direct interactions between NSCs and BV mural cells (endothelial cells and peri-
cytes), with functional implications in the developing nervous systems, is only now
starting to be elucidated. The vascularisation of the forebrain begins after NEP cells
have formed the VZ and it progresses first at the pial surface (around E9) and sub-
sequently at the periventricular domains (around E11) (Tan et al. 2016 ; Vasudevan
et al. 2008 ). Descriptive analyses have now convincingly shown that RGC basal
processes remain in contact with BVs throughout the forebrain (Vasudevan et al.
2008 ) and that intermediate progenitors, which form the SVZ, are positioned and
undergo mitoses in close proximity to BVs (Javaherian and Kriegstein 2009 ). The
latter could be of significance in the rodents, in which intermediate progenitors (a)
lack the capacity to produce ECM (in contrast to NSCs of the VZ) (Fietz et al.
2012 ), (b) lack processes that are in contact with the pial basement membrane.
Therefore, the basement membrane of BVs (Tan et al. 2016 ) might be offering nec-
essary extracellular cues. Recent experimental work revealed that specifically in the
ventral telencephalon and in a gradually increasing proportion of RGCs, the basal
process does not anchor at the pial surface, but rather to the basement mabrane of
E. Andreopoulou et al.