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First published online 23 April 2008
doi: 10.1242/dev.018119
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-subunit in neuromuscular synaptic patterning
1 Department of Neuroscience, UT Southwestern Medical Center, 5323 Harry Hines
Blvd, Dallas, TX 75235-9111, USA.
2 Centre National de Genotypage, 91057 Evry Cedex, France.
3 Department of Neurobiology, The University of Chicago, Chicago, IL, USA.
4 Department of Biology, University of Utah, Salt Lake City, UT, USA.
5 Department of Pharmacology and Physiology, UMDNJ-New Jersey Medical School,
Newark, NJ, USA.
* Author for correspondence (e-mail: weichun.lin{at}utsouthwestern.edu)
Accepted 11 April 2008
Formation of the vertebrate neuromuscular junction (NMJ) takes place in a
stereotypic pattern in which nerves terminate at select sarcolemmal sites
often localized to the central region of the muscle fibers. Several lines of
evidence indicate that the muscle fibers may initiate postsynaptic
differentiation independent of the ingrowing nerves. For example, nascent
acetylcholine receptors (AChRs) are pre-patterned at select regions of the
muscle during the initial stage of neuromuscular synaptogenesis. It is not
clear how these pre-patterned AChR clusters are assembled, and to what extent
they contribute to pre- and post-synaptic differentiation during development.
Here, we show that genetic deletion of the AChR 
-subunit gene in mice
leads to an absence of pre-patterned AChR clusters during initial stages of
neuromuscular synaptogenesis. The absence of pre-patterned AChR clusters was
associated with excessive nerve branching, increased motoneuron survival, as
well as aberrant distribution of acetylcholinesterase (AChE) and rapsyn.
However, clustering of muscle specific kinase (MuSK) proceeded normally in the
-null muscles. AChR clusters emerged at later stages owing to the
expression of the AChR epsilon-subunit, but these delayed AChR clusters were
broadly distributed and appeared at lower level compared with the wild-type
muscles. Interestingly, despite the abnormal pattern, synaptic vesicle
proteins were progressively accumulated at individual nerve terminals, and
neuromuscular synapses were ultimately established in -null muscles.
These results demonstrate that the -subunit is required for the
formation of pre-patterned AChR clusters, which in turn play an essential role
in determining the subsequent pattern of neuromuscular synaptogenesis.
Key words: Neuromuscular junction, Nicotinic acetylcholine receptor, Synaptic patterning, Synaptogenesis
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