Molecular Biology of the Cell by Bruce Alberts, Alexander Johnson, Julian Lewis, David Morgan, Martin Raff, Keith Roberts, Peter Walter by by Bruce Alberts, Alexander Johnson, Julian Lewis, David Morg

1210 Chapter 21: Development of Multicellular Organisms
motor axon
Schwann
cell
muscle fiber
synaptic vesicles
pre-synaptic
membrane
(A)
basal
lamina
basal
lamina
muscle
fiber
acetylcholine
receptor
post-synaptic
membrane
(D)
1 µm
(B)
(C)
Formation of the synapse involves two-way communication between the
muscle cell and axonal growth cone: each of them, under the influence of the
other, must reorganize the molecules on its side of the junction. The growth cone
releases the signal protein Agrin, while the muscle expresses the Agrin receptor
LRP4. Agrin binding to LRP4 stimulates association of LRP4 with MuSK, a receptor
tyrosine kinase. LRP4 also serves as a signal in the reverse direction, from the
MBoC6 n22.240/22.83
muscle to the axon (Figure 21–83). During synapse formation, MuSK and LRP4
cluster in the muscle cell plasma membrane in the general neighborhood of the
future synapse. As the growth cone approaches, it recognizes LRP4, which stimulates
the differentiation of presynaptic structures in the nerve cell. At the same
time, Agrin released from the growth cone binds to LRP4 in the muscle cell; this
activates MuSK, and promotes a more focused clustering of acetylcholine receptors
in the muscle cell membrane. Through these mechanisms, the reciprocal signaling
of LRP4 from muscle to growth cone—and of Agrin from growth cone to
muscle—induces the coordinated, localized differentiation of pre- and postsynaptic
structures.
Synapse formation between neurons in the CNS is far more challenging, both
for the neurons and for the scientists trying to understand the molecular basis of
its specificity, and it remains poorly understood.
Figure 21–82 Formation of the
neuromuscular junction. (A) The growth
cone of a motor axon approaches the
muscle fiber. (B) Initial synapse formation
is characterized by the accumulation of
synaptic vesicles at the axon terminal
and the formation of a specialized basal
lamina in the synaptic cleft. (C) As the
neuromuscular junction matures, the
synaptic cleft accumulates basal lamina
and extracellular matrix proteins, synaptic
vesicles cluster at presynaptic release sites,
and neurotransmitter receptors cluster at
postsynaptic sites. Schwann (glial) cells
accompany the motor axon and wrap
around its terminus outside the region of
synaptic contact. (D) Transmission electron
micrograph of the region of synaptic contact.
[D, courtesy of John Heuser, from J. Electron
Microsc. 60 (Suppl 1), 2011. With permission
from Oxford University Press.]
axon of motor neuron
LRP4 SIGNALS
BACK TO AXON
Agrin
axon
terminal
axon terminal
Agrin
muscle
fiber
basal
lamina
new
synapse
muscle fiber
acetylcholine
receptor
LRP4
MuSK
(C)
(A)
CLUSTERING OF
LRP4 AND MuSK
BY AGRIN
MuSK
(Agrin
co-receptor)
LRP4
(Agrin
receptor)
CLUSTERING OF
ACETYLCHOLINE
RECEPTORS
(B)
Figure 21–83 Reciprocal signaling during neuromuscular synapse differentiation. (A) The Agrin receptor LRP4 and its co-receptor MuSK
cluster in the muscle cell membrane in the general neighborhood of the future synapse. (B) As the growth cone approaches, it recognizes LRP4,
which stimulates differentiation of presynaptic structures. Reciprocally, Agrin is released from the nerve terminal, binds to a complex of LRP4 and
MuSK in the muscle, and (C) promotes the further and more focused clustering of the LRP4 and acetylcholine receptors in the muscle cell. Although
the Agrin/MuSK/LRP4 machinery organizes the synapse, the process also depends on electrical signaling via the acetylcholine receptors. It is not
yet known how LRP4 signals to the motor axon.
MBoC6 n22.241/22.84