Failure of postsynaptic specialization to develop at neuromuscular junctions of rapsyn-deficient mice

Abstract

OF numerous synaptic components that have been identified, perhaps the best-studied are the nicotinic acetylcholine receptors (AChRs) of the vertebrate neuromuscular junction¹. AChRs are diffusely distributed on embryonic myotubes, but become highly concentrated (~ 10,000 µm-2) in the postsynaptic membrane as development proceeds. At least two distinct processes contribute to this accumulation. One is local synthesis: subsynaptic muscle nuclei transcribe AChR subunit genes at higher rates than extra-synaptic nuclei, so AChR messenger RNA is concentrated near synaptic sites^2,3. Second, once AChRs have been inserted in the membrane, they form high-density clusters by tethering to a sub-synaptic cytoskeletal complex. A key component of this complex is rapsyn, a peripheral membrane protein of relative molecular mass 43K (refs 4, 5), which is precisely colocalized with AChRs at synaptic sites from the earliest stages of neuromuscular synaptogenesis⁶. In heterologous systems, expression of recombi-nant rapsyn leads to clustering of diffusely distributed AChRs, suggesting that rapsyn may control formation of clusters^7,8. To assess the role of rapsyn in vivo, we generated and characterized mutant mice with a targeted disruption of the Rapsn gene. We report that rapsyn is essential for the formation of AChR clusters, but that synapse-specific transcription of AChR subunit genes can proceed in its absence.