Brain Development
119
dorsal root ganglia (DRG).
In vitro
ex-
periments have revealed that SemaD ex-
pressing cells indeed repel or collapse
growth cones from DRG neurons, whereas
growth cones from DRG neurons isolated
from NP-1 gene targeting mice cannot be
affected by SemaD expressing cells.
In
vivo
, efferent axons from the NP-1 mu-
tant DRG were found to be defasciculated
and/or harbor excess spreading, suggest-
ing an important role for NP-1/SemaD
in constituting the guidance pathway. The
NP-1/SemaD interactions also appear to
regulate the initial patterning of projec-
tions from neocortical neurons: cortical
neurons expressing NP-1 sense the SemaD
signal from the marginal zone, sending
efferent axons to avoid the SemaD signals.
Receiving
various
contact-dependent
and contact-independent signals and/or
cues, migrating growth cones sum up
these stimulations and determine the Fnal
direction to go. Such decisions are mainly
made within the cytoplasm of growth
cones, and small signaling molecules
play major roles. ±or example, VAB-8,
a cytoplasmic protein with kinesin mo-
tor similarity, is normally required for
the posterior axon guidance in
C. elegans
,
and ectopic expression of VAB-8 has been
shown to be sufFcient to totally reverse
the direction of axon outgrowth. The ra-
tios of activity of a cytoplasmic tyrosine
kinase, ABL, its substrate ENA, and the
tyrosine phosphatases, which antagonize
ENA, have also been demonstrated to be
balanced by various Robo mediated guid-
ance signals and Fnally set a direction to
go. Activity and/or localization of a second
messenger such as cyclic-AMP and cyclic-
GMP have further been revealed to affect
the Fnal direction to go in
Xenopus
spinal
axons and the cortical efferents respec-
tively. Regarding the turning response of
growth cones, local activation of the Rho
family of GTPases, which is able to re-
arrange the cytoskeltal organization, has
been implicated. ±or instance, Eph/ephrin
interactions could modulate Rho activity,
yet the detailed machinery that link dis-
tinct GTPases to other guidance cues is
not well understood.
It should be apparent that the molecular
mechanisms involved in axon guidance
are used in controlling the direction of
cellular migrations. ±or instance, the Eph-
ephrin repulsive signals together with the
cadherin-mediated cell adhesion machin-
ery play a crucial role in generating cell
lineage restriction between neuromeres
(see above). Neural crest cells also require
Eph/ephrin signaling, when they migrate
from the dorsal neural tube and travel to-
ward their Fnal locations. ±urthermore,
the rostral migration stream from the gan-
glionic eminence to the olfactory bulb
in the forebrain as well as the cytokine
induced leukocytes migration has been
shown to be dependent on Slit signaling.
Such cellular machineries are so impor-
tant that they might repeatedly be utilized
during development and evolution.
6.3
Plasticity of the Neuronal
Circuit-potentiation of Synaptic
Transmission
Here, I just outline the molecular mech-
anisms involved in the potentiation of
synaptic transmission, because detailed
mechanisms have been well summarized
in a chapter of the previous series written
by Dr Eric Kandel and references therein.
As I described earlier, it has been re-
ported that the morphological as well as
physiological features of synaptic junc-
tions can vary over time in the mature
brain. ±or instance, if an excitory presy-
naptic neuron is artiFcially stimulated at
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