Formation and maintenance of neuromuscular synaptic connections

Texas A&M University, College Station TX

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Abstract

Our previous work has shown that the glia (Schwann cells, SCs) at the neuromuscular junction (NMJ) participate in the removal of polyneuronal innervation during early postnatal development in mice. They do this by interposing themselves between the nerve terminals and the muscle fibers and by phagocytosis of the nerve terminals themselves. However, what is unclear is what causes these SCs to behave in this destructive manner. Our hypothesis is that some signal, likely from the nerve, engages this activity and that this signal is developmentally regulated. Here we propose a series of experiments that follow up on preliminary results that strongly suggest that the nerve membrane-linked isoform of a trophic factor called neuregulin 1 type III might play this role. Schwann cells are known to be responsive to this signaling. We propose to use light microscopy, electron microscopy, molecular biology, and physiology to examine the developmental expression of this isoform during early postnatal development and the consequences of manipulating the expression of this isoform, and its receptor by use of transgenic and knockout mice. If our hypotheses are correct, then the display of neuregulin by motor axons to receptive SCs is at least part of the mechanism controlling the behavior of these cells at the synapse. Not only will these findings add to the existing knowledge about the roles of neuregulin in trophic maintenance and myelination activity of SCs, they will also suggest mechanisms by which these glial cells might participate in events that compromise synaptic function during aging, neuromuscular disease, and repair of nerve injuries.