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gene in a transgenic mouse, the result is the expression
of BDNF throughout the inner ear, and all the fibers
that normally innervate the NT-3 rich areas survive
and innervate the cochlea as usual (Tessarollo et al.,
2004). So the neurotrophic factors can substitute for
each other in a way. However, these transgenic mice
show excessive innervation of the cochlea from
neurons that would normally innervate the vestibular
regions, a miswiring that probably occurs because the
changed spatiotemporal expression pattern of BDNF.
This incorrect projection can be enhanced by knocking
out the normal expression of BDNF in the vestibular
region. These results suggest that correct temporal and
spatial pattern of neurotrophin expression may be
critical for the correct innervation of these inner-ear
A Wild type
Inner ear primordium
Mature inner ear
B TrkB, TrkC double mutant
No innervation
C BDNF replaces NT-3
In the previous chapter, we discussed how the
axons of retinal ganglion cells navigate to their targets
in the optic tectum. In this chapter, we discuss how
these axons find their postsynaptic targets within the
tectum. The ability to look at these processes as they
are happening has been important in establishing
some aspects of targeting. For example, time-lapse
observations of fluorescently labeled RGC axons in
Xenopus embryos grow at a rate of about 60 um/hr in
the optic tract but slow to about 16 um/hr when they
enter the optic tectum (Harris et al., 1987) (Figure 6.5).
Once within the optic tectum, these terminals may
advance in a saltatory, stop and start, manner. Why do
growth cones slow down when they reach tectum?
Retinal axons grow toward their target on a pathway
that is rich in FGF, and this molecule has been found
to promote axonal growth in the tract and in vitro. As
retinal axons enter the tectum, they encounter a
sudden drop in external FGF because the tectum
expresses very little of it (McFarlane et al., 1995).
Therefore, one cue that decreases the growth rate of
retinal axons at the target is a drop in FGF levels. If
excess FGF is added, or if the retinal axons are made
insensitive to FGF, the retinal axons do not respond to
the target and often grow by it, so they may read the
drop in FGF as a target entry signal (McFarlane et al.,
1995; McFarlane et al., 1996; Webber et al., 2003).
As retinal growth cones slow down in the tectum,
time-lapse images show that they also become much
more complex. Branches begin to form, and many of
these arise at some distance behind the axonal tip
(Harris et al., 1987). Thus, axonal arbors are built in a
way that is reminiscent of the way the arbor of a tree
To o much
cochlear innervation
FIGURE 6.4 Innervation of the inner ear is regulated by BDNF
and NT-3. A. In the-wild-type animal, the vestibulo-cochlear gan-
glion, all of whose neurons express TrkB and TrkC, grow toward the
developing inner ear, which has a vestibular and a cochlear pri-
mordium. As the system develops and the primordia develop into
semicircular canals and a cochlea, the ingrowing axons innervate
both parts of the inner ear. B. In BDNF, NT-3 or TrkB, TrkC double
mutants, the inner ear remains uninnervated. C. In transgenic mice
in which BDNF has been knocked into the NT-3 coding region, the
cochlear region becomes innervated by the vestibular part of the
ganglion. (After Ernfors et al., 1995; Fritzsch et al., 1997; Fritzsch
et al., 2004; Tessarollo et al., 2004)
NT-3 is also expressed in the developing inner ear, and
all the innervating fibres possess receptors for both
neurotrophins: Trk-B for BDNF and Trk-C for NT-3.
Knockout experiments of the ligands show that BDNF
is necessary for the innervation of the vestibular hair
cells, whereas NT-3 is more important in the innerva-
tion of the cochlear hair cells, for that is where these
factors are most heavily expressed (Fritzsch et al.,
1997). In mice that lack both BDNF and NT-3, or both
TrkB and TrkC, there is a complete loss of innervation
to the inner ear (Fritzsch et al., 1997). Interestingly, if
the BDNF coding sequence is inserted into the NT-3
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