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ing development by regulating processes such as progenitor cell proliferation,
migration, differentiation and synapse formation (Zimmermann 2006 ). During the
development of the cortex, ATP released through connexin hemichannels in RG
activates P2Y1 receptors generating a Ca2+ wave by IP3 mediated Ca2+ release that
propagates among neighboring RG (Weissman et al. 2004 ). These Ca2+ waves regu-
late the proliferation of RG and have been proposed as a mechanism for synchroniz-
ing the cell cycle of a cohort of progenitors (Weissman et al. 2004 ). Purinergic
signaling leads to the expansion of the ventricular zone stem cell niche (Lin et al.
2007 ) and can initiate important events as transient release of ATP triggers the
development of the eye by inducing the expression of Pax6 via P2Y1 receptor acti-
vation (Massé et al. 2007 ). In addition, nucleotide signaling seems also to partici-
pate in adult neurogenesis as the ATP hydrolyzing ectonucleotidase NTPDase2 is a
hallmark of adult neurogenic niches (Abbracchio et al. 2006 ). However, the detailed
function of ATP signaling in regulating adult stem cell niches is still poorly
understood.
Different kinds of insults are linked to increased levels of extracellular ATP.
For example, after spinal cord injury (SCI) ATP levels increase around the lesion
epicenter (Wang et al. 2004 ). It has been proposed that ATP may act as a diffusible
“danger signal” to alert about damage and start repair (Abbracchio et al. 2009 ).
Purinergic signaling has been also implied in the secondary expansion of tissue
damage after SCI (Wang et al. 2004 ; Peng et al. 2009 ). CSFcNs have P2X2 recep-
tors (Stoeckel et al. 2003 ) that when activated by ATP generates a powerful excita-
tion (Marichal et al. 2009 ).
The P2X7 receptor merits particular attention in relation to CNS injury. P2X7
receptors have the peculiarity of having a rather low sensitivity being activated at
100 μM to 3 mM of ATP whereas other P2X receptors have EC50 of 1–10 μM
(Khakh and North 2006 ; Surprenant and North 2009 ). In addition, P2X7 are highly
permeable to Ca2+ and when activated for several seconds become permeable to
the large cation N-methyl-D-glucamine (Surprenant et al. 1996 ). Ependymal cells
in both the medial (Fig. 5.5a, b) and lateral (Fig. 5.5c, d) domains of the CC have
functional ionotropic P2X7 receptors (Masahira et al. 2006 ). The activation of
P2X7 receptors by ATP or its selective agonist BzATP generates a slow inward
current and a Ca2+ wave that propagates bidirectionally from the site of ATP appli-
cation (Fig. 5.5). It is possible that P2X7 receptors may be a key component of the
response of the ependymal stem cell niche to spinal cord injury. The activation of
P2X7 receptors in the distal processes lying within injured tissue would generate
a Ca2+ wave propagating towards the CC, generating a local Ca2+ increase in key
cellular compartments such as the nucleus and the apical process of CC-contacting
progenitors (Fig. 5.6). Ca2+ transients may modulate nuclear gene expression, acti-
vating or repressing function-specific transcription factors that may affect events
such as proliferation, differentiation and migration (Glaser et al. 2013 ; Miras-
Portugal et al. 2015 ) of ependymal cells. For example, interference of Ca2+ signal-
ing by blockade or genetic knockdown of purinergic receptors impairs the
migration of intermediate neuronal progenitors to the subventricular zone (Liu
et al. 2008 ). Ca2+ waves propagated to or generated at the apical pole of
N. Marichal et al.