Brain Development
117
it is known that sugar groups could
modify the N-CAM extracellular domain
(polysialylated form; PSA-N-CAM). This
modiFcation lowers the binding afFnity,
providing repulsive cues for axon guid-
ance. TAG-1/axonin-1 and L1 with six Ig
domains show a curious expression pat-
tern during the axon guidance process:
The commissural neurons of the verte-
bra
tesp
ina
lcordFrs
tsendaxonstoward
the floor plate and the axons cross the mid-
line at the floor plate. After crossing the
midline, the axons immediately change di-
rection by 90
to ascend the spinal cord
(±ig. 10c). While TAG-1 expression is de-
tected during the initial axon guidance
process and is downregulated after the
turning, L1 expression is only switched on
after the turning (±ig. 10c). This indicates
that localization and/or expression of guid-
ance molecules even along the same axon
could be tightly regulated, allowing growth
cones to sense various environmental cues
over time and space. Interestingly, TAG-1
is known to heterotypically interact with
Nr-CAM (Ng-CAM related Ig superfamily
adhesion molecule), which is expressed by
the floor plate cells. Such molecular inter-
actions occurring at a restricted territory
per se
might have a role in changing the
growth cone behaviors.
6.1.2
Integrins
Integrins are the cell surface receptors and
their substrates are the ECM molecules
such as laminin, Fbronectin, and so on.
Integrins consist of two subunits, namely,
α
-and
β
-chains. Distinct genes encode
α
-a
n
d
β
-chains, and differential com-
binations of
α
/
β
-chains produce various
afFnities to ECM ligands/substrates. In
the CNS, multiple types of receptors and
their substrates are expressed, and prefer-
ential interactions between integrins and
molecules in the ECM are indeed shown
to play essential roles in guiding neurites
in vitro
. The cytoplasmic domain of inte-
grins is known to interact with cytoskeletal
elements, such as vinculin, talin, and
α
-
actinin, each of which is found to localize
at the growth cones. Importantly, integrins
have been shown to play a major role in
directed cell migration by remodeling the
cytoskeltons, and migration of mouse cor-
tical neurons has been demonstrated to
be dependent of integrins. Mechanisms
that regulate cellular migrations would
be utilized in the directed steering of
axons.
6.1.3
Cadherins
Cadherins are transmembrane proteins
that confer subclass speciFc adhesiveness
to cells: cells that express one particu-
lar subclass can generally contact with
tho
seth
a
te
xp
re
s
sthes
amesub
c
l
a
s
sin
aCa
2
+
dependent manner. Takeichi and
colleagues Frst demonstrated that func-
tional neuronal circuits in the chicken
nervous system were subdivided by differ-
ential expressions of N- and R-cadherin.
In the mouse thalamocortical connection
system, expressions of type II cadherins
have also been shown to delineate the spe-
ciFc division in the thalamus as well as the
neocortical area. ±urthermore, cadherin-6
expression was found to demarcate entire
parts of the neuronal circuit such as the au-
ditory circuit. Redies and colleagues have
revealed that such differential expression
patterns along the neuronal circuit play a
crucial role in Fnally targeting the axons
into a speciFc area by means of the EP
mediated cadherin overexpression exper-
iment. In the
Drosophila
embryo, it has
also been shown that
D
N-cadherin plays a
role in the segregation of axon tracts in a
fascicle, otherwise the neural circuits were
totally disorganized.
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