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In-Depth Information
CHAPTER
5
Axon Growth and Guidance
Newborn neurons send out processes, threadlike
axons that carry information to target cells and den-
dritic processes that receive inputs from other neurons.
Some neurons, local interneurons, have short axons
and make connections to cells in their immediate vicin-
ity, while others, projection neurons, send long axons
to distant targets. There is tremendous divergence and
convergence of wiring. On the sensory side, peripheral
neurons send axons into the CNS where they usually
diverge to project to several distinct targets. Each of
these targets contains neurons that also diverge to
various targets of their own, and so on. Tracing path-
ways from the motor side backwards yields a similar
complexity in convergence, with each motor neuron
being innervated by many presynaptic neurons, and
each of these having its own multitude of inputs. Thus,
with thousands of target nuclei and billions of axons,
the interweaving of axonal pathways is a remarkably
complex tapestry. When looking at an adult brain, it is
difficult to imagine how the precise patterns of con-
nections were ever made. However, by looking at early
embryonic brains, there is the possibility of seeing
the very first axons on their way (Wilson et al., 1990;
Ross et al., 1992; Easter et al., 1994) (Figure 5.1). These
pioneer axons navigate in a simpler environment. But
as the brain matures, more axons are added, and the
weave becomes more intricate. As these later axons
navigate, they are aided by pathways laid down by
earlier axons. In this way, the rich tapestry of the brain
wiring is accomplished by successive addition of new
fibers that add complexity in a stepwise fashion.
An illustrative example of pioneer axonal naviga-
tion is that of the sensory neurons that arise in the
distal part of a grasshopper leg (Keshishian and
Bentley, 1983a, b, c). These cells, called Ti's, pioneer the
tract that later developing sensory axons will follow to
their targets in the central nervous system. If these Ti
pioneers are ablated with a laser, then the later axons
cannot find their way into the CNS. But how do the
Ti's find their way in the first place? Part of the answer
is that the Ti's use local cues on their journey. Spaced
at short distances from one another are a series of well-
spaced “guidepost” cells for which the Ti growth cones
show a particular affinity (Caudy and Bentley, 1986).
The distances between guideposts are small enough
that a growth cone can reach out to a new guidepost
while still contacting the previous one. Ti axons thus
use these guidepost cells as stepping-stones into the
CNS (Figure 5.2). Some of the guideposts are critical
for pathfinding because when they are obliterated
with a laser microbeam, the Ti axons get stuck and
are unable to make it from one segment to the next
(Bentley and Caudy, 1983).
An important insight into axonal navigation came
from a simple experiment performed by Hibbard
(Hibbard, 1965). He rotated a piece of the embryonic
salamander hindbrain. In this tissue there are a pair of
giant neurons called Mauthner cells that are respon-
sible for rapid escape response. These neurons send
large diameter axons, easily visible with silver stain-
ing, caudally down the spinal cord. In the rotated piece
of hindbrain, Hibbard saw the axons of Mauthner cells
initially grew rostrally instead of caudally, as though
they were guided by local cues within the transplant.
However, when the axons of these rotated neurons
reached the rostral boundary of the transplant and
entered unrotated neural tissue, they made dramatic
U-turns and headed caudally down toward the spinal
cord. This proved that axon navigation relies on cues
provided by the external environment and is not just
an intrinsic program of directions (Figure 5.3).
The axon of a projection neuron makes a journey to
connect to its distant target much like a driver makes
a journey from a particular address in one populated
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