Evidence for Muscle-Dependent Neuromuscular Synaptic Site Determination in Mammals
Recent evidence challenges 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 model in which the muscle fiber induces a nascent postsynaptic apparat...
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Published in | The Journal of neuroscience Vol. 28; no. 12; pp. 3123 - 3130 |
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Main Authors | , , |
Format | Journal Article |
Language | English |
Published |
United States
Soc Neuroscience
19.03.2008
Society for Neuroscience |
Subjects | |
Online Access | Get full text |
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Summary: | Recent evidence challenges 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 model in which the muscle fiber induces a nascent postsynaptic apparatus and sets the location of the future synapse. On axonal contact, these sites, laid out in a prepattern in the central area of developing muscle fibers, mature into synapses by the combined action of neural factors such as agrin and ACh. We sought to test in mammals these two models of neuromuscular synaptogenesis. Previously, we showed that continuous prenatal muscle expression of constitutively active ErbB2 (CAErbB2) led to synaptic loss, exuberant axonal sprouting, and lethality at birth. Here, we transiently induced CAErbB2 during midgestation and examined synapse restoration after inducer withdrawal. Centrally enriched ACh receptor (AChR) transcription and clustering were abolished after transient CAErbB2 induction. After inducer withdrawal, synapses were restored but were distributed widely over the entire diaphragm muscle. Under the nerve-dependent model, this distribution is explained by the wide pattern of axonal sprouting triggered by CAErbB2. Yet, in the absence of the nerve, introduced in our animals by mating to Hb9(+/-) mice, a very similar, wide distribution of aneural AChR clusters resulted. Thus, transient expression of CAErbB2 in skeletal muscles leads to reprogramming of the endogenous muscle AChR prepattern. This, and not the nerve, seems primarily responsible for the widely distributed pattern of synapses in our experimental animals. |
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Bibliography: | ObjectType-Article-2 SourceType-Scholarly Journals-1 ObjectType-Feature-1 content type line 23 V. M. Vock's present address: Department of Cell Biology, University of Virginia, Charlottesville, VA 22908. |
ISSN: | 0270-6474 1529-2401 |
DOI: | 10.1523/JNEUROSCI.5080-07.2008 |