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stretch receptor
NGF dependent (nocioreceptive or
thermoreceptive neuron)
SEMA III expression
motor neuron
EphrinA5, NT-3
In vitro NGF dependent
CGRP-positive sensory
neurons growing away from
COS cells
to cortex
to thalamus
Layer 2/3
Layer 5
SEMA III knockout
Thalamic axons
Later 2/3 neurons
CGRP-expressing neuron
in mutant
Later 6 neurons
FIGURE 6.22 Layer-specific targeting in the sensory cortex.
A. Thalamic and Layer 6 axons invade the cortex and selectively
branch in Layer 4, which expresses Ephrin-A5 and NT-3. The
branches of Layer 2/3 neurons avoid Layer 4. B. In vitro studies
show that Ephrin-A5 and NT-3 enhance growth and branching of
thalamic and Layer 6 neurons, but inhibit the growth of Layer 2/3
neurons. There is also in vitro evidence to suggest that the mem-
branes of Layer 2/3 and Layer 5 cells are specifically inhibitory to
the growth of thalamic and Layer 6 axons.
FIGURE 6.21 The role of Sema3A in keeping some axons out of
a target region. A. Stretch receptors project their central axons into
the ventral horn of the spinal cord where they synapse on motor
neuron dendrites. Nocioreceptive and thermoreceptive axons,
which are NGF dependent, however, terminate in the dorsal gray
matter of the spinal cord. Sema3A is expressed only in the ventral
cord. B. COS cells in culture repel nocioceptive and thermoreceptive
axons from DRG cultures. C. In Sema3A knockout mice, these
sensory neurons extend into the ventral horn. (After Messersmith et
al., 1995)
2/3 cells in the cortex send out axons that do not branch
in layer 4. For the axons of layer 2/3 cells, in vitro
experiments show that Ephrin-A5 inhibits rather than
promotes branching. Interestingly, NT-3, which is
expressed in layer 4, also promotes axonal branching of
layer 6 axons while it inhibits branching of layer 2/3
axons (Castellani and Bolz, 1999). Finally, it has been
shown that blocking impulse activity in the cortex also
impairs the selective branching of layer 6 axons in layer
4. In summary, these studies demonstrate that many
familiar factors are at work, leading to laminated projec-
tions, and that some factors may have bifunctional roles
in promoting the branching of some axons and inhibit-
ing the branching of others.
Laminar-selective growth is even more impressive
in the chick tectum where there are 16 layers that
receive input from at least 10 different sources. The
retinal ganglion cells contribute input to just three of
these layers, and each retinal ganglion cell sends its ter-
minals to just one of these three layers. These retinore-
cipient layers express a number of molecules including
different layers. The different layers of the cortex are
innervated by different inputs. In vitro studies using
membrane fractions of cells in the different layers
suggest that the targeting cues are membrane-associ-
ated (Castellani and Bolz, 1997). Somatosensory thala-
mic neurons, for example, innervate layer 4 of the
somatosensory cortex and cross through layer 5 without
branching (Bolz et al., 1996) (Figure 6.22). Ephrin-A5 is
expressed on the membranes of cells in layer 4 but not
layer 5, and in vitro studies show that membrane-bound
Ephrin-A5 increases the branching of thalamic axons
and that there are as yet unidentified repulsive activities
to these neurons on the membranes of layers 2/3 and 5
cells (Mann et al., 2002b). Layer 6 neurons in the cortex,
like thalamic cells, also arborize in layer 4, and some
results suggest that the axons of these neurons respond
to Ephrin-A5, as do thalamic axons (Castellani et al.,
1998). Unlike the thalamic cells and layer 6 cells, layer
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