Terminal Schwann cells that cap neuromuscular junctions (NMJs) are proposed to play important roles in the formation, maintenance and regeneration of peripheral motor synapses. At adult NMJs, terminal Schwann cells and their processes cover precisely axon terminal branches that lie juxtaposed to acetylcholine receptors located on the postsynaptic muscle fiber membrane. Following muscle denervation, normally quiescent terminal Schwann cells (SCs) become 'reactive' a phenotype characterized by the growth of SC processes, SC proliferation, SC migration from synapses and the induction of nerve terminal sprouting. These morphological changes greatly enhance the re-establishment of severed motor synapses by creating a microenvironment that supports the efficient regeneration of motor axons. Uncovering the molecular mechanisms that allows these cells to switch from the quiescent, nerve bound SC to the reactive, denervated SC is the focus of my investigation. One strategy for increasing understanding of the roles of SCs in regeneration is to manipulate the expression of genes known to regulate SC function.

In this study, I have used the Tet-On system of gene expression to conditionally regulate the expression of a constitutively active form of the Nrg receptor, ErbB2 thus allowing me to artificially drive neuregulin signaling selectively in SCs of transgenic mice. My results show that Nrg signaling in SCs can account for many of the morphological changes observed in terminal SCs following muscle denervation. In addition, I show that rescue of neonatal SCs from denervation induced apoptosis involves autocrine signaling by Nrg. Taken together, my results suggest that SCs can dramatically alter synaptic architecture and that Nrg is the likely signal causing the reactive SC phenotype following muscle denervation.