Restoration of synapse formation in Musk mutant mice expressing a Musk/Trk chimeric receptor

Mice lacking Musk, a muscle-specific receptor tyrosine kinase that is activated by agrin, fail to form neuromuscular synapses and consequently die at birth because of their failure to move or breathe. We produced mice that express a chimeric receptor, containing the juxtamembrane region of Musk and the kinase domain of TrkA, selectively in muscle, and we crossed this transgene into Musk mutant mice. Expression of this chimeric receptor restores presynaptic and postsynaptic differentiation, including the formation of nerve terminal arbors, synapse-specific transcription, and clustering of postsynaptic proteins, allowing Musk mutant mice to move, breathe and survive as adults. These results show that the juxtamembrane region of Musk, including a single phosphotyrosine docking site, even in the context of a different kinase domain, is sufficient to activate the multiple pathways leading to presynaptic and postsynaptic differentiation in vivo. In addition, we find that Musk protein can be clustered at synaptic sites, even if Musk mRNA is expressed uniformly in muscle. Moreover, acetylcholine receptor clustering and motor terminal branching are restored in parallel, indicating that the extent of presynaptic differentiation is matched to the extent of postsynaptic differentiation.