118
Brain Development
6.2
Contact-independent (Long-range) Axon
Guidance Mechanisms
Many secreted molecules and their lig-
ands play a central role in steering axon
guidance. For example, interneurons in
the vertebrate spinal cord send the com-
missural axons toward the ventralmost
midline cells, the floor plate. Growth cones
then cross the midline and project anteri-
orly as shown in Fig. 10(c). In the frst
step o± these processes,
Netrin
secreted
±rom the floor plate has been shown to
have an activity that attract the growth
cone expressing the receptor DCC (D
eleted
in C
olorectal C
ancer), an Ig super±am-
ily molecule with ±our Ig domains and
six FNIII repeats. Netrin was originally
identifed as the gene responsible ±or the
unc
oordinated cell migration phenotype
(unc-6) in
C. elegans
, and importantly, it is
known that Netrin can ±unction as a repel-
lant i± the DCC receptor interacts with an-
other receptor UNC-5. The trochlear motor
neurons are located in the ventral region
o± the hindbrain and send axons dorsally.
Netrin has indeed been shown to regulate
this axon guidance step in a repulsive man-
ner, yet the receptor components in this
process are not confrmed to be UNC-5 de-
pendent. Recently, the
Drosophila
Netrin
receptor Frazzled (
Drosophila
DCC ho-
molog) has been demonstrated to guide
axons by controlling Netrin distribution.
In this model, Netrin captured and re-
located by the receptor Frazzled along
the pioneer axon, could ±urther act as
a contact-dependent attractive guidance
cue ±or growth cones expressing unknown
Netrin receptors other than Frazzled, im-
plicating complex molecular machineries
involved in the Netrin-mediated axon guid-
ance (Fig. 10a).
The secreted molecule Slit can act as a
repellant and the receptor is an Ig super-
±amily member Roundabout (Robo) with
fve Ig domains and three FNIII repeats.
In
Drosophila
,S
l
itisexpressedattheven
-
tral midline cells and this prevents axons
that had once crossed the midline ±rom
recrossing it (Fig. 10d). There±ore, growth
cones in the Slit receptor Robo mutants
cross the midline many times (Fig. 10d).
Notable is the ±act that growth cones a±-
ter crossing the midline become sensitive
to Slit repulsive cues in the wild type,
although the Robo mRNA is expressed
by almost all neurons be±ore crossing the
midline (Fig. 10d). It is revealed that a
transmembrane protein, Commissureless
(Comm), transiently inactivates the Robo
protein until growth cones cross the mid-
line, otherwise axons can never cross the
midline because o± the repulsive activity o±
Slit, resulting in the commisureless phe-
notype in the mutant (Fig. 10d). As the
Robo protein is ±ound to be sequestered in
the internal vesicles o± growth cones be±ore
crossing the midline, Comm might regu-
late the localization o± the Robo protein
during axon guidance. Robo has ±urther
been demonstrated to be able to interact
with DCC, the Netrin receptor. This in-
teraction has been shown to be essential
not only to silence the Netrin attractive
signals but also to potentiate the Slit
repulsive signals a±ter crossing the mid-
line.
Semaphorins are another type o± se-
creted molecule, and both neuropilins and
plexins are the receptor components o±
semaphorins. In the mouse, neuropilin-
1 (NP-1) is a known receptor component
o± SemaphorinD (SemaD; the human ho-
molog is named SemaphorinIII, while the
chicken homolog is termed CollapsinI)
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