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The Journal of Neuroscience, March 19, 2008, 28(12):3123-3130; doi:10.1523/JNEUROSCI.5080-07.2008

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Development/Plasticity/Repair
Evidence for Muscle-Dependent Neuromuscular Synaptic Site Determination in Mammals

Vita M. Vock,¹ Olga N. Ponomareva,¹ and Mendell Rimer^1,2

¹Section of Neurobiology, University of Texas at Austin, Austin, Texas 78712, and ²Department of Neuroscience and Experimental Therapeutics, College of Medicine, Texas A&M Health Science Center, College Station, Texas 77843

Correspondence should be addressed to Mendell Rimer, Department of Neuroscience and Experimental Therapeutics, College of Medicine, Texas A&M Health Science Center, 228 Reynolds Building, College Station, TX 77843-1114. Email: mjrimer{at}medicine.tamhsc.edu

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.

Key words: acetylcholine receptor; motoneuron; muscle fiber; agrin; neuromuscular junction; synaptogenesis

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Received Nov. 15, 2007; revised Feb. 6, 2008; accepted Feb. 7, 2008.

Correspondence should be addressed to Mendell Rimer, Department of Neuroscience and Experimental Therapeutics, College of Medicine, Texas A&M Health Science Center, 228 Reynolds Building, College Station, TX 77843-1114. Email: mjrimer{at}medicine.tamhsc.edu

This article has been cited by other articles:

				S. Lin, M. Maj, G. Bezakova, J. P. Magyar, H. R. Brenner, and M. A. Ruegg Muscle-wide secretion of a miniaturized form of neural agrin rescues focal neuromuscular innervation in agrin mutant mice PNAS, August 12, 2008; 105(32): 11406 - 11411. [Abstract] [Full Text] [PDF]

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