Nitric Oxide Mediated Signal Transduction in Networks of Human ...

1994; Santacana et al., 1998; Chen et al., 2004; Nott and Riccio, 2009). In line with this, NO has
been shown to suppress the proliferation of neural precursor cells in developing Drosophila
imaginal disks (Kuzin et al., 1996; Enikolopov et al., 1999), Xenopus tadpole optic tectum
(Peunova et al., 2001, Peunova et al., 2007) and cerebellar granule cells of new born rats (Ciani et
al., 2006). In developing chicken neural tube NO is endogenously produced which has been
proposed to regulate cell-cycle progression. It has been demonstrated that high NO levels promoted
entry into S phase basally, whereas low levels of NO facilitated entry into mitosis apically (Traister
et al., 2002). Moreover, in cultured human neuroblastoma cell lines NO has been showed to inhibit
neuronal precursor cell proliferation (Murillo-Carretero et al, 2002; Ciani et al., 2004). Treatment
of dissociated mouse cortical neuroepithelial cluster cell cultures and rat cerebellar granule cells
with NOS inhibitor or scavenging of NO resulted in enhanced proliferation (Cheng et al., 2003;
Ciani et al., 2004). These studies show the anti-proliferative role of endogenous NO in neuronal
precursor cells; however, the mechanism is not fully understood. In developing Xenopus, cerebellar
granule cells and human neuroblastoma cells, the cGMP/PKG pathway has been suggested to
mediate the anti-proliferative role of NO (Peunova et al., 2007; Ciani et al., 2004; Ciani et al.,
2006). In both cerebellar cells and neuroblastoma culture the oncogenic transcription factor, N-
Myc, has been shown to be over expressed due to down regulation of cGMP/PKG pathway
(Contestabile A., 2008). On the contrary, other studies demonstrated that the anti-proliferative effect
of NO is cGMP independent (Phung et al., 1999; Young et al., 2000; Gibbs, 2003).
1.2.2. Neuronal migration
Neurons and neuronal precursor cell migrate long distances along the dorsal-ventral and anterior-
posterior axes of the nervous system during the early embryonic period, which is important for the
formation of functional neuronal network. Two modes of neuronal migration has been identified:
radial migration, in which cells migrate from the progenitor zone toward the surface of the brain
following the radial layout of the neural tube; and tangential migration, in which cells migrate
orthogonally to the direction of radial migration (Hatten, 1999; Marin and Rubenstein, 2003; Ayala
et al., 2007; Metin et al., 2008). In the developing rat brain, nNOS reaches the highest expression
level between embryonic day 16 and postnatal day 0, and this expression corresponds with the
migration of neuronal precursors from the ventricular zone to the external layers of the cortex
(Bredt and Snyder, 1994; Nott et al., 2008).
The first functional evidence on the role of NO in neuronal migration came from study conducted
on migrating granule cells of rat (Tanaka et al., 1994). The migration of cerebellar granule cells was
decreased in the presence of NOS inhibitor or haemoglobin that scavenges NO (Tanaka et al.,
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