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and Notch signaling was also shown to regulate quiescence of NSCs at the cell
contact between NSCs and endothelial cells, mediated by Jagged1 expression on
endothelial cells (Ottone et al. 2014 ). Canonical Notch signaling has been shown to
be crucial for regulating quiescence and activation of NSCs by additional experi-
mental work. Deletion of Rbpj forced NSCs to progress in the lineage producing
type C and A cells, eventually depleting their pool (Imayoshi et al. 2010 ). Moreover,
conditional deletion of Notch1 affected activated NSCs, but spared quiescent NSCs
(Basak et al. 2012 ). An interesting link between notch signalling and the activity of
PEDF, a factor well-described to affect NSC self-renewal in the SEZ (Ramírez-
Castillejo et al. 2006 ), was reported with PEDF inducing symmetric cell divisions
downstream of notch (Andreu-Agulló et al. 2009 ).
An important aspect of the neurogenic activity of the SEZ is the migration of
neuroblasts to the olfactory bulbs. The direction of movement of neuroblasts is
guided by the direction of movement of the CSF, controlled by ependymal cilia
(Sawamoto et al. 2006 ). Netrins have been identified as potent modulators of neuro-
blast migration, since netrin-1 is expressed by olfactory bulb cells and netrin recep-
tors, such as neogenin and DCC, are expressed on type A cells (Astic et al. 2002 ;
Murase and Horwitz 2002 ). Although the regulation of neuroblast migration and
differentiation is still largely unknown, neogenin has also been shown to synchro-
nize their migration and their terminal differentiation by affecting cell cycle kinet-
ics, similar to cannabinoids’ activity through the PKC-dependent phosphorylation
of fascin (O’Leary et al. 2015 ; Sonego et al. 2013 ).
6.3.1.6 Neurotransmitters and Neuromodulators
Because cytogenesis in the SEZ is known only to supply new neurons and oligoden-
drocyte progenitors in the olfactory bulbs and the corpus callosum, respectively,
neurotransmission wasn’t expected to play a significant regulatory role. Nevertheless,
augmenting evidence suggests the contrary. An interesting hypothesis is that dopa-
minergic regulation of proliferation in the SEZ allows the niche to communicate
with the periphery. A downside of this system is that in pathologic conditions of loss
of dopaminergic innervation, as observed in Parkinson’s disease, NSC self-renewal
and progenitor proliferation is disturbed (O’Keeffe et al. 2009b). Dopaminergic
regulation appears to be EGF-dependent and FGF2-independent (O’Keeffe et al.
2009b), and most of the experimental data converge on a key role of D1, D2 and D3
receptors (Kim et al. 2010 ; Lao et al. 2013 ; O’Keeffe et al. 2009a). Specifically for
D3 receptors, they are specifically expressed on type C cells (Kim et al. 2010 ) and
their activation induces NSC self-renewal and type-C cell generation through Akt
and ERK1/2 signaling (Lao et al. 2013 ). A role for cholinergic neurotransmission
was also suggested when researchers identified a population of choline acetyltrans-
ferase (ChAT) positive neurons in the rodent SEZ with a morphology distinct to
those of the striatum (Paez-Gonzalez et al. 2014 ). Neuroblast generation could be
modulated using optogenetic tools in order to induce or block cholinergic activity,
and it was shown that response to Ach was mediated through FGFRs (Paez- Gonzalez
E. Andreopoulou et al.