93Patched it led to a transient increase in proliferation followed by exhaustion of type
B1 cells (Daynac et al. 2016 ). Shh signalling has been shown to be more significant
in two domains of the SEZ: at the dorsal, subcallosal, ventricular wall, where it
transiently controls oligodendrogenesis during early postnatal stages (Tong et al.
2015 ) and at the ventral SEZ where its activity depends on the function of primary
cilia (Tong et al. 2014b).
Another family of molecules known to control proliferation and cell fate of stem
and progenitor cells during development are bone morphogenetic proteins (BMP).
The low density lipoprotein receptor-related protein 2 (LRP2), an endocytic recep-
tor for BMP4, is specifically expressed in ependymal cells of the SEZ and lack of
expression in adult mice leads to impaired proliferation of neural progenitors
(Gajera et al. 2010 ). Other experiments revealed that exogenous BMPs limit the
EGF-induced proliferation of type C cells, while inhibition of BMP-SMAD signal-
ling promoted activation of quiescent NSCs. Therefore, correct tuning of BMP and
EGF activity is necessary for the regulation of NSC quiescence and transit amplify-
ing progenitor mitotic activity (Joppé et al. 2015 ). Moreover, induced over-
expression of Noggin, a secreted BMP inhibitor, in ependymal cells or in NSCs led
to enhanced proliferation of transit amplifying progenitors and favoured oligoden-
drogenesis (Lim et al. 2000 ; Morell et al. 2015 ). The binding of BMPs to fractones
(exemplified by BMP-4) has been suggested as one mechanism for regulating their
local activity (Mercier and Douet 2014 ). Finally, in the ependymal of the post-injury
spinal cord, anchoring of the BMP type 1b receptor subunit into lipid rafts is con-
trolled by β1-integrin; thus, providing a mechanism of regulating BMP-dependent
astrogliogenesis by NSCs (North et al. 2015 ).
In vitro studies have shown that different members of the int/Wingless (Wnt)
family of morphogens can promote proliferation and either neuronal (Wnt3a,
Wnt5a) or oligodendroglial (Wnt3a) differentiation of SEZ-derived NSC cultures
(Ortega et al. 2013 ; Yu et al. 2006 ) and transcripts for these factors have been identi-
fied in the SEZ and adult OB (Shimogori et al. 2004 ). Notably, the transcription of
Axin2, a target of the canonical Wnt signalling pathway, is active in type B, type C,
but not type A cells; hence, suggesting distinct functions of Wnt signalling in differ-
ent progenitors (Adachi et al. 2007 ). Non-canonical Wnt signalling has also been
shown to function in the SEZ, since diversin is expressed in type A cells and its
overexpression increases their proliferation (Ikeda et al. 2010 ).
Several Eph tyrosine kinase receptors and their ephrin ligands, as well as mul-
tiple components of the Notch signaling are present in the SEZ. Holmberg and col-
leagues (Holmberg et al. 2005 ) identified an ephrin-A2/Eph A7 feedback system,
operating between progenitors of different maturity in the SEZ in order to control
proliferation and cell generation capacity. Ephrin-A and B signaling has been shown
to positively regulate NSC proliferation within the SEZ as well as the cellular archi-
tecture and the migration of neuroblasts in the RMS (Conover et al. 2000 ; Todd
et al. 2017 ). In 2008, the intriguing ability of SEZ NSCs to regenerate low levels of
ependymal cell damage was revealed (Luo et al. 2008 ). Few years later, EphB2
signaling was found to mediate this type of plasticity, with astrocytes becoming
ependymal cells and vice versa (Nomura et al. 2010 ). Recently, the Eph/ephrinB2
6 Being a Neural Stem Cell: A Matter of Character But Defined...