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Netrin-1 expression pattern in the floorplate
A
Brain
Dorsal
commissural
interneurons
Trigeminal
ganglion
Maxillary
pad
Floorplate
In vitro assay of floorplate & Netrin-1
Neighboring
epithelia
tissuel
B
C
Dorsal
interneurons
Dorsal neural tube
Dorsal neural tube
Dorsal neural tube
FIGURE 5.30 Chemotactic agents from target tissues. Sensory
axons from the trigeminal ganglion heavily innervate the maxillary
pad of the mouse face, the site of the whisker field. When the trigem-
inal ganglion is placed into a three-dimensional collagen gel with
the maxillary pad tissue and another piece of epithelium, the axons
leaving the ganglion grow toward their appropriate target, suggest-
ing that it is releasing a chemotropic agent. (After Lumsden and
Davies, 1986)
Directed axon
outgrowth
floorplate
Netrin-expressing
COS cell line
Asuggestion for a diffusible guidance mechanism
also came from work in nematodes. Here a gene called
unc-6 is expressed at the ventral midline, and unc-6
mutants show the circumferential guidance defects of
certain axons toward the ventral midline (Hedgecock
et al., 1990; Culotti, 1994). Nematodes with a deletion
of the unc-40 gene also show defects in the migration
of neuronal processes toward the ventral midline.
Unlike unc-6 mutants, the unc-40 phenotype is cell
autonomous, with unc-40 being expressed in the nav-
igating axons. This suggests that Unc-40 might be a
receptor for Unc-6. The first diffusible axon attractant
identified turned out to be a homolog of Unc-6. In
the spinal cord of vertebrates, dorsal commissural
interneurons grow to the ventral midline, cross the
floorplate, and then turn 90° and grow in a longitudi-
nal tract beside the floorplate. Two factors were bio-
chemically purified from embryonic chick brains using
a bioassay for directed outgrowth from commissural
interneurons in explants of dorsal spinal cord. They
were partially sequenced, and the genes encoding
these proteins were pulled out of a cDNA library
(Kennedy et al., 1994; Serafini et al., 1994). They were
called netrin-1 and netrin-2 after the Sanskrit “netr,”
meaning “one who guides.” In the spinal cord netrin-
1 is expressed in the floor plate (Figure 5.31). The
netrins are secreted molecules found largely attached
FIGURE 5.31 Dorsal commissural interneurons are attracted by
a gradient of netrin. A. Dorsal commissural interneurons grow
directly to the ventral midline of the spinal cord along a gradient of
netrin that is released by floorplate neurons. B. In collagen gels,
dorsal interneurons are attracted at a distance to the floorplate.
C. They are also attracted to netrin released from a pellet of COS
cells which have been transfected with the netrin gene. (After
Kennedy et al., 1994)
to cell membranes, but they are somewhat diffusible
and can clearly reorient growing commissural axons
toward a local source of netrin over a distance of hun-
dreds of microns (Colamarino and Tessier-Lavigne,
1995) (Figure 5.31). In netrin-1 knockout mice, the
dorsal commissural interneurons of the spinal cord do
not grow all the way toward the ventral midline.
Netrins have also been found in Drosophila where they
serve a similar role in guiding commissural axons to
the ventral midline. The sequence of the netrin gene
showed it to be a homolog of the nematode gene unc-
6 (discussed below). In vertebrates, DCC binds netrin,
is expressed in commissural interneurons, and is
essential for the attraction of their axons to the floor-
plate (Keino-Masu et al., 1996). The DCC protein,
which is a transmembrane receptor, is a homolog of the
nematode Unc-40 (Chan et al., 1996). A mutation in the
Drosophila netrin receptor homolog, which is called
 
 
 
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