Evidence for muscle-dependent neuromuscular synaptic site determination in mammals

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Vock, Vita Marie, 1963-

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Recent evidence has challenged the prevalent view that neural factors induce the formation of a de novo postsynaptic apparatus during development of the vertebrate neuromuscular junction. The latest experiments suggest an alternative, muscle-dependent model in which the muscle induces the nascent postsynaptic apparatus and sets the location of the future synapse. Once contacted by the incoming axons, these sites, laid out in a pre-pattern in the central area of developing muscle fibers, mature into synapses by the combined action of neural factors such as agrin and ACh. In this study, I sought to provide a test in mammals for these two models of neuromuscular synaptogenesis. Previously, our laboratory showed that continuous muscle expression of constitutively active ErbB2 (CAErbB2) during embryogenesis leads to synaptic loss, exuberant axonal sprouting and lethality at birth. Here, I transiently induced CAErbB2 during midgestation and examined the process of synapse restoration after inducer withdrawal. Centrallyenriched AChR transcription and AChR clustering were abolished as a result of transient CAErbB2 induction. After inducer withdrawal, synapses were restored but were distributed widely over the entire surface of the diaphragm. Under the nerve-dependent model, this distribution would have been explained by the wide pattern of axonal sprouting triggered by CAErbB2 expression. Yet, in the absence of the nerve, introduced in our transgenic animals by mating to Hb9+/- mice, a very similar, wide distribution of aneural AChR clusters was generated. Thus, even in a case where the central pre-pattern of AChR transcription and clustering is missing, it is the muscle, and not the nerve, that seems to set the site for synapse formation. My results support a muscle-dependent model for the induction of neuromuscular synaptogenesis in mammals.



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