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A
B
Pontine growth cones
Gr cells
presynaptic
scaffold
Frizzled
microtubules
Wnt-7a
b- Neurexin
vesicles
postsynaptic
scaffold
FIGURE 8.13 Signals that promote differentiation of growth cones into presynaptic boutons.
A. Pontine growth cones (arrows) stop when they contact granule cells (arrowhead) in a dissociated culture
system. B. Pontine growth cones express two receptors, frizzled and b-neurexin, on their surface. Granule
cells express their respective ligands: Wnt-7 and Neuroligin-1. These signaling pathways recruit synaptic vesi-
cles and presynaptic proteins to the site of contact. (Panel A from Baird et al., 1992)
Neuroligin-1
cell-autonomous process, or is it induced by the presy-
naptic terminal? At first inspection, the postsynaptic
site appears to be produced in an autonomous fashion.
Structures that resemble postsynaptic densities, but
that do not appear to contact a presynaptic element,
have also been found in the developing olfactory bulb
and visual cortex during early development (Hinds and
Hinds, 1976; Bahr and Wolff, 1985). In fact, most neuro-
transmitter receptors are expressed before innervation
occurs; they can even be found in clusters, similar in
appearance to a postsynaptic site (Figure 8.4A). Acetyl-
choline receptors (AChRs) also form small clusters on
the muscle cell membrane even before the motor axon
terminals arrive (Fischbach and Cohen, 1973).
At the time of innervation, the muscle cell membrane
still displays an immature distribution of AChRs. This
was originally demonstrated by recording the response
from rat muscle cells in vivo as ACh was applied at dif-
ferent places along the myofiber surface (Diamond and
Miledi, 1962). Early in development, ACh application at
each site evokes a similar shift in membrane potential.
As the muscle became innervated, the ACh-evoked
response becomes much larger at the site of innerva-
tion, and the response at extrasynaptic regions declines.
Soon after, it became possible to visualize the distri-
bution of AChRs by labeling them with radioactive a-
bungarotoxin (a-Btx), a high-affinity peptide from the
venom of the Taiwanese cobra (Bevan and Steinbach,
1977; Burden, 1977a). Consistent with the electrophysi-
ological measures, a-Btx labeling is broadly distributed
at first and then became highly localized to the synapse.
The process of clustering leads to a dramatic disparity
in receptor concentration: there are >10,000
AChRs/mm 2 at the synaptic region but <10/mm 2 in
extrasynaptic regions (Fertuck and Salpeter, 1976;
Burden, 1977a; Salpeter and Harris, 1983).
While these observations suggested that the motor
axons induce receptor clustering, higher AChR concen-
trations occur at the center of skeletal muscle fibers
in the absence of motor innervation. In HB9 mutant
mice, the phrenic nerve fails to develop, and the dia-
phragm muscle remains uninnervated during embry-
onic development (Yang et al., 2001). Despite this,
AChRs are concentrated in the central region of the
muscle by E18.5 (Figure 8.15). However, there are signs
that a motor terminal does organize postsynaptic struc-
ture from the earliest stage. Drosophila muscle fibers
produce tiny processes, called myopodia , that interact
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