Nerve terminals form but fail to mature when postsynaptic differentiation is blocked: In vivo analysis using mammalian nerve-muscle chimeras

To better understand the role of the postsynaptic cell in the differentiati on of presynaptic terminals, we transplanted muscles that lacked postsynapt ic differentiation from mutant mice into normal adult immunocompatible host s and attached the host nerve to the grafts. Host motor axons innervated wi ld-type grafted muscle fibers and established normal appearing chimeric neu romuscular junctions. By repeated in vivo imaging, we found that these syna pses were stably maintained. Results were different when nerves entered tra nsplanted muscles derived from mice lacking muscle-specific receptor tyrosi ne kinase (MuSK) or rapsyn, muscle-specific components required for postsyn aptic differentiation. Initial steps in presynaptic differentiation (e.g., formation of rudimentary arbors and vesicle clustering at terminals) occurr ed when wild-type neurites contacted MuSK- or rapsyn deficient muscle fiber s, either in vivo or in vitro. However, wild-type terminals contacting MuSK or rapsyn mutant muscle fibers were unable to mature, even when the chimer as were maintained for up to 7 months. Moreover, in contrast to the stabili ty of wild-type synapses, wild-type nerve terminals in mutant muscles under went continuous remodeling. These results suggest that postsynaptic cells s upply two types of signals to motor axons: ones that initiate presynaptic d ifferentiation and others that stabilize the immature contacts so that they can mature. Normal postsynaptic differentiation appears to be dispensable for initial stages of presynaptic differentiation but required for presynap tic maturation.