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Ta rget Selection
As a growth cone nears the end of its journey, it
must find appropriate target cells with which to
synapse. This has to be done with immense accuracy
because a properly functioning nervous system
depends on precise patterns of neural connectivity.
The task seems daunting because the growth cone
may be confronted with thousands or even millions of
roughly similar cells in the general target area from
which it will have to choose only one or a few as post-
synaptic partners. The process of target selection can
be broken down into a number of conceptual steps
(Holt and Harris, 1998) (Figure 6.1). First, as they near
the target area, axons defasciculate from the tracts or
nerves that they are growing along. Next, they enter
the target area, slow down, and begin searching for
their postsynaptic partners who might also be search-
ing, via dendritic growth, for the axons that will inner-
vate them. As they search, the axon terminals begin to
branch in the target area. Molecular barriers may be
erected around the borders of the target area so that
the incoming axons are corralled until they find the
most suitable partners. In large target areas, there is
often a topographic mapping strategy so that the axon
and its postsynaptic partner can meet at particular
molecular coordinates. Some targets are multilayered,
and it is important for axons to find the appropriate
synaptic layers within the correct topographic region.
Having finally arrived at the correct location, the
growing axons choose particular postsynaptic cells
and perhaps particular dendrites or regions of these
There is a final phase of target selection, which has
to do with the refinement of connections and is often
based on neuronal activity and dependent on synapse
formation (see Chapter 8). As synapses are formed, the
nervous system can begin to function and test out the
wiring for connections that are misplaced. This func-
tional verification of target selection is used to refine
the connections further so that the end product works
in the real world. The refinement of connections is
dealt with more thoroughly in Chapter 9. The consid-
eration of target selection as the product of a series of
discrete decisions makes it easier to appreciate how
immense precision can be developmentally built into
the nervous system.
In order to enter a target area or to find a target cell
with which to make synapses, it is often first necessary
to exit from a tight bundle. Nerves, tracts, columns,
bundles, and fasciculi often travel past a variety of
potential targets. As they do so, specific axons or
groups of axons peel off of these common pathways,
so that they can enter the target. In the last chapter, we
saw that homophilic adhesion molecules such as N-
CAM and its homologs can cause similar axons to fas-
ciculate together into nerves or tracts in the nervous
system, and so one of the first questions in targeting is
how do axons leave these tracts and nerves? How do
they defasciculate? Changes in cell adhesion seem nec-
essary. In Drosophila, there is a mutant called beaten path
in which motor axons fail to defasciculate from the
main nerve and as a result bypass their targets (Vactor
et al., 1993). The protein encoded by this gene, Beat-1a,
thus seems required for selective defasciculation of
motor axons at these choice points. Indeed, Beat-1a
appears to be an anti-adhesion factor that is secreted
by growth cones (Fambrough and Goodman, 1996).
There are other Beat-family members, such as Beat-Ic,
which are not secreted but are membrane-bound pro-
teins that have pro-adhesive functions (Pipes et al.,
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