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normal mouse
Ta rgets can be internal organs, sensory cells,
muscles, or other neuronal nuclei in CNS or PNS.
What makes these tissues the targets for specific inner-
vation? The sympathetic nervous system, with its
diversity of end organs, provides an excellent oppor-
tunity to study this question. For sympathetic neurons,
neurotrophins are the key to initial innervation. There
are several different neurotrophins, originally named
for their effects on neuronal growth and survival. In
Chapter 7, we will see that the survival of sympathetic
and other neurons is critically dependent on receiving
enough of these target-derived trophic factors.
However, the axons must first enter the targets to gain
access to a supply of the neurotophins, and neu-
rotrophins like NGF have roles in target entry that are
distinct from their roles in survival (Glebova and
Ginty, 2004). Many sympathetic neurons grow along
vasculature to reach their various somatic targets.
These blood vessels are a source of the neurotrophin,
NT-3. In the absence of NT-3, sympathetic cells often
fail to invade their targets (Kuruvilla et al., 2004). Take,
for example, the epidermis of the external ear. It is
innervated by sympathetic neurons, and in NT-3
knockout mice, sympathetic fibers fail to invade the
external ear postnatally. Exogenously administered
NT-3 into the ear rescues the sympathetic innervation
of the mutant mice (ElShamy et al., 1996) (Figure 6.3).
When sympathetic fibers get right into the target
region, they often switch the neurotrophin they are
most interested in from NT-3 to NGF (Kuruvilla et al.,
2004). The pancreas and other internal organs, which
are invaded by different sets of sympathetic fibers,
express NGF, which is critical for target invasion. If
NGF is overexpressed under the control of a beta-cell
specific promoter in the islets of the pancreas in trans-
genic mice, there is a dramatic increase in the inner-
vation of the islets (Hoyle et al., 1993). The role of NGF
in attracting innervation has medical implications. For
example, pancreatic cancer is particularly invasive to
neural tissue, and this may be because it attracts inner-
vation (Schneider et al., 2001). Similarly, pancreatic
transplants may benefit by the local application of
NGF to help attract innervation (Reimer et al., 2003).
Amore interesting example of target recognition by
sympathetic axons concerns another neurotrophin,
glial-derived neurotrophic factor (GDNF) (Ledda et
al., 2002). GDNF is recognized by the c-Ret receptor on
the growth cones of innervating axons, and it is also
recognized by a GPI-linked secreted receptor called
GFRal. The peripheral targets of the c-Ret expressing
axons, such as the epidermis, secretes GFRa1, which
sympathetic axons invade external ear
NT3 knock out
fibers do not invade
NT3 knock out with NT3 injection: Fibers invade again
FIGURE 6.3 Some sympathetic neurons use a change in NT-3
expression to innervate their targets in the ear. A. Some SCG neurons
project to and arborize in the pinna of a normal mouse. B. In NT3
knockout mice, these fibers do not invade the pinna. C. Restoration
of targeting by injection of NT3 into the ear. (Adapted from ElShamy
et al., 1996)
captures circulating GDNF and holds it to the target
sites, thus creating a very high level of GDNF right
around the target, which attracts innervation from
c-Ret expressing axons.
Neurotrophins are also involved in the innervation
neuronal targets by nonsympathetic neurons. A par-
ticularly interesting example is the innervation of
the inner ear, which includes the vestibular organs of
balance and the cochlear organs of hearing (Ernfors
et al., 1995), (Figure 6.4). Neurotrophins are first
expressed in the otocyst during the time at which gan-
glion cells with neurotrophin receptors send their
processes toward this structure. Indeed, BDNF may
be expressed by the hair cells, which are the cellular
targets of this innervation, well before the hair cells
have fully differentiated (Hallbook and Fritzsch, 1997).
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