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A
Motor neuron
Muscle fiber
P4
d
b
P9
g
g
P16
a
a
g
g
g
e
e
e
e
B
+Neuregulin
Control
e
a
g
e
a
g
protein
mRNA
nucleus
FIGURE 8.27 Substitution of ACh receptors subunit during development. A. In rat muscle, AChRs are
composed of a, b, d, and g subunits at postnatal (P) day 4. By P9, there are a mix of receptors: some have the
initial complement of subunits, and other have substituted the e subunit in place of the g subunit. At P16, all
receptors contain the e subunit. B.Neuregulin selectively upregulates the transcription of e subunit mRNA.
In control muscle cell cultures, approximately equal amounts mRNA for the e, g, and a AChR subunits are
produced. The addition of neuregulin increases mRNA for all subunits, but the e subunit is selectively
enhanced. (Adapted from Gu and Hall, 1988 and Martinou et al., 1991)
1979). A 42 kD glycoprotein was isolated from the chick
central nervous system, and subsequently found to be
a member of the Neu protooncogene ligand family
(Usdin and Fischbach, 1986; Falls et al., 1993; Jo et al.,
1995). In the nervous system, members of this protein
family are now referred to as the neuregulins (NRGs),
and they play a broad role in neural development,
including migration and glial differentiation (Chapters
3 and 4). More than 20 NRG1 isoforms are produced
from the single NRG1 gene. The receptors for neureg-
ulins are actually members of another large family: the
EGF receptor tyrosine kinase family (erbBs). At the
neuromuscular junction, NRG-1 co-localizes with at
least three of these erbB receptors. Neuregulin signal-
ing may involve a common kinase pathway. In one cell
line, neuregulin stimulates tyrosine phosphorylation of
erbBs and mitogen-activated protein kinase (MAPK).
Furthermore, a specific inhibitor of MAPK abolishes
neuregulin-induced AChR subunit expression (Si et al.,
1996).
NRG1 message is localized to motor neuron cell
bodies, and the protein is transported to the synaptic
junction. Electron microscopic images show that
NRG1 becomes concentrated on the presynaptic side
of the basal lamina after it is released at the neuro-
muscular junction (Goodearl et al., 1995). NRG1
remains in the synaptic basal lamina even after dener-
vation (Falls et al., 1993; Sandrock et al., 1995; Jo et al.,
1995). The NRG-erbB signaling pathway is recruited,
in part, by Agrin. Even in the absence of nerves, Agrin
is able to cluster both NRG and erbB in muscles (Rimer
et al., 1998). Furthermore, one of the NRG receptors,
erbB3, does not accumulate at synapses in rapsyn -/-
mice (Moscoso et al., 1995).
The increase in AChR synthesis results largely from
an accumulation of mRNAs for specific AChR sub-
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