Our previous work has shown that the glial (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 there is some signal, likely from the nerve, that 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, its receptor, and the enzymes that process the isoform 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.
During the previous grant period, we found that glial cells at the synapse between motor neurons and muscle fibers participate in the reduction in the number of these synapses (synapse elimination) during early postnatal development by interposing themselves into the space between the cells and by consuming nerve terminals. This proposal seeks to investigate the signaling that enables this behavior of the glial cells because they are not active in this way in the normal adult. We believe these glial cells play important roles in synaptic changes that occur in aging, in muscular dystrophy, and in repairs that occur after nerve injury and that understanding this signaling will aid in the treatment of these changes.
