116
Brain Development
6.1
Contact-dependent (Short Range) Axon
Guidance Mechanisms
In chicken embryos, the retinal ganglion
cells in the eye send axons toward a
midbrain region, the tectum. Noticeable
is the fact that the connection pattern be-
tween the retina and the tectum is totally to-
pographic; nasal ganglion cells send axons
to the posterior tectum and the temporal
ones to the anterior tectum. Furthermore,
the dorsal ganglion cells send axons to
the ventral tectum and the ventral ones to
the dorsal tectum, enabling them to sim-
ply relay the two-dimensional information
caught by an eye to the brain (Fig. 10b).
To precisely establish such a connection
pattern, Eph tyrosine kinase receptor, and
its ligand ephrin have been shown to play
a crucial role: EphA3 expression makes
a gradient along the nasal–temporal axis
in the retina (higher in the temporal;
see Fig. 10b) while the ligand ephrinA2/5
makes a gradient along the A–P axis in
the tectum (higher in the posterior; see
Fig. 10b). The interactions between Eph
and ephrin cause the collapse of growth
cones, steering the axon into the area
with less interactions between the recep-
tor and the ligand. The same mechanism
seems to be utilized in the thalamocorti-
cal projections in mice, as EphrinA2 and
A5 expression make a gradient in the
thalamic lateral geniculate nucleus, and
EphrinA2/A5doublemutantmicehavede-
fects in this connection system. Regarding
the upstream factors required to regulate
the EphA3 gradient in the chicken retina
along the nasal-temporal axis, transcrip-
tion factors such as CBF-1/2 are known
to make a similar gradient to EphA3. Ec-
topic expression of CBF-1/2 in the retina
has been shown to perturb the topo-
graphic retina–tectum projection patterns,
implicating these molecules in the impor-
tant role of axon guidance. However, there
is no evidence that these transcription fac-
tors directly regulate EphA3 expression
and there could be additional uncharac-
terized mechanisms. In the tectum, FGF8
and Wnt1 expression at the MHB is known
to be required to set up an expression gra-
dient of transcription factors Engrailed1/2
along the A–P axis, controlling the gradual
expression of ephrinA2 and A5 (Fig. 8a).
Other important molecules steering the
growth cone in a contact-dependent man-
ner are cell adhesion molecules. Cell ad-
hesion molecules could further be a com-
ponent to stabilize the synaptic junctions
immediately after the axon guidance pro-
cesses. There are three major types of cell
adhesion molecules: (1) immunoglobulin
(Ig) superfamily molecules, (2) integrins,
and (3) cadherins. The following is a brief
summary of the roles of these classes of
adhesion molecules in axon guidance:
6.1.1
Ig Superfamily Molecules
Ig superfamily molecules are simply de-
±ned by containing the Ig domain folded
by a disul±de link. Numbers of Ig super-
family molecules with multiple Ig domains
are expressed in the CNS. The smallest
Ig superfamily molecule expressed in the
CNS is Thy-1, which contains just one
Ig domain. Thy-1 is a major fraction of
thesu
r
facep
ro
te
inonlongaxons
,s
tab
i
-
lizing the membrane to prevent neurite
sprouting during the guidance process. N-
CAM (Neural cell adhesion molecule) has
±ve Ig domains and two ±bronectin type
III (FNIII) repeats, and its expression is
found everywhere in the CNS, providing a
good neural marker during development.
In vitro
assay showed that homophilic
interaction between axons and cell sub-
strates expressing N-CAM is crucial to
promote axon outgrowth. Interestingly,
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