Joined the Department in 2013
- Ph.D., 1975, University of California, Berkeley, Molecular Biology
- Postdoctoral research, Institute of Physiology in Oslo, Norway.
- Postdoctoral research, Department of Physiology and Biophysics, Washington University School of Medicine
All neuroscientists agree that the brain functions by virtue of the way its neurons are wired together in intricate circuits. I study how these connections between neurons, i.e. synapses, are formed and maintained. I study the simplest of all vertebrate synapses, the neuromuscular junction (NMJ). This synapse, the connection between a motor neuron and a skeletal muscle fiber, offers a number of advantages for the types of questions that interest me. The synapse is huge, easily accessible, and easily manipulated. There is only a single “pre-synaptic” input and the target cell is very large. This is in contrast to most synapses in the central nervous system where the pre- and post-synaptic elements are very small and the numbers of synapses and cells closely packed together are enormous. There are a number of neurological disorders that affect the integrity of this synapse or its components.
The specific issue that I pursue is the role of the glial cells that are present at this synapse. At the NMJ there are several Schwann cells (the glial cells of the peripheral nervous system or PNS) that are in intimate contact with the terminal branches of each motor neuron. If a muscle is denervated by crushing the muscle nerve, the Schwann cells react to the degeneration of the axons and nerve terminals by growing long, elaborate processes that extend away from the synaptic site. Motor axons regenerate quite readily and Schwann cell processes serve as substrates for the regrowing axons. In this way, the Schwann cells apparently determine where in the muscle regenerating axons grow.
In my lab we image Schwann cells and axons in living mice to determine the relationships between axons and Schwann cells at normal NMJs as well as during reinnervation and sprouting. For this purpose, we have made transgenic mice in which green fluorescent protein (GFP) is expressed in Schwann cells. We have mated these animals to animals obtained from collaborators in which cyan fluorescent protein (CFP), is expressed in axons. In this way we produce mice bearing two transgenes. We can stain the acetylcholine receptors with small concentrations of a snake toxin, bungarotoxin, that is conjugated to a red fluorochrome, rhodamine. Thus, we can insert a microscope objective into a small lesion in the skin of a mouse and observe green Schwann cells, blue axons and axon terminals, and red acetylcholine receptors. Moreover, each site bears a “fingerprint” that one can easily use to identify this same synaptic site hours, days, weeks, months, or even years later. Thus, it is possible to identify the synaptic components at individual synapses and see how they change with time. We are investigating how motor neurons regenerate and sprout in the muscle in response to nerve injury. In this way, we are learning exactly the relationships between axons and their glial cells as synapses reform.
We are also examining and manipulating the molecules involved in this relationship between glia and nerve terminals. We have made transgenic mice in which a target gene in Schwann cells can be turned on at the will of the investigator by simply giving the mouse an oral antibiotic. The system works well and we are now embarking on experiments to express proteins that we believe are crucial for the function of these cells.
In summary, research in my lab uses imaging and mouse transgenic technology to explore mechanisms involved in synaptic maintenance and in repair of neuronal lesions.
- Lee, YI, Thompson, WJ, Harlow, ML. Schwann cells participate in synapse elimination at the developing neuromuscular junction. Curr. Opin. Neurobiol. 2017;47 :176-181. doi: 10.1016/j.conb.2017.10.010. PubMed PMID:29121585 PubMed Central PMC5732880.
- Lee, YI, Li, Y, Mikesh, M, Smith, I, Nave, KA, Schwab, MH et al.. Neuregulin1 displayed on motor axons regulates terminal Schwann cell-mediated synapse elimination at developing neuromuscular junctions. Proc. Natl. Acad. Sci. U.S.A. 2016;113 (4):E479-87. doi: 10.1073/pnas.1519156113. PubMed PMID:26755586 PubMed Central PMC4743767.
- Kang, H, Tian, L, Mikesh, M, Lichtman, JW, Thompson, WJ. Terminal Schwann cells participate in neuromuscular synapse remodeling during reinnervation following nerve injury. J. Neurosci. 2014;34 (18):6323-33. doi: 10.1523/JNEUROSCI.4673-13.2014. PubMed PMID:24790203 PubMed Central PMC4004816.
- Smith, IW, Mikesh, M, Lee, Yi, Thompson, WJ. Terminal Schwann cells participate in the competition underlying neuromuscular synapse elimination. J. Neurosci. 2013;33 (45):17724-36. doi: 10.1523/JNEUROSCI.3339-13.2013. PubMed PMID:24198364 PubMed Central PMC3818548.
- Li, Y, Lee, Yi, Thompson, WJ. Changes in aging mouse neuromuscular junctions are explained by degeneration and regeneration of muscle fiber segments at the synapse. J. Neurosci. 2011;31 (42):14910-9. doi: 10.1523/JNEUROSCI.3590-11.2011. PubMed PMID:22016524 PubMed Central PMC3213690.
- Li, Y, Thompson, WJ. Nerve terminal growth remodels neuromuscular synapses in mice following regeneration of the postsynaptic muscle fiber. J. Neurosci. 2011;31 (37):13191-203. doi: 10.1523/JNEUROSCI.2953-11.2011. PubMed PMID:21917802 PubMed Central PMC3181159.
- Ellerton, EL, Thompson, WJ, Rimer, M. Induction of zinc-finger proliferation 1 expression in non-myelinating Schwann cells after denervation. Neuroscience. 2008;153 (4):975-85. doi: 10.1016/j.neuroscience.2008.02.078. PubMed PMID:18440155 .
- Hayworth, CR, Moody, SE, Chodosh, LA, Krieg, P, Rimer, M, Thompson, WJ et al.. Induction of neuregulin signaling in mouse schwann cells in vivo mimics responses to denervation. J. Neurosci. 2006;26 (25):6873-84. doi: 10.1523/JNEUROSCI.1086-06.2006. PubMed PMID:16793894 .
- Zuo, Y, Lubischer, JL, Kang, H, Tian, L, Mikesh, M, Marks, A et al.. Fluorescent proteins expressed in mouse transgenic lines mark subsets of glia, neurons, macrophages, and dendritic cells for vital examination. J. Neurosci. 2004;24 (49):10999-1009. doi: 10.1523/JNEUROSCI.3934-04.2004. PubMed PMID:15590915 .
- Love, FM, Son, YJ, Thompson, WJ. Activity alters muscle reinnervation and terminal sprouting by reducing the number of Schwann cell pathways that grow to link synaptic sites. J. Neurobiol. 2003;54 (4):566-76. doi: 10.1002/neu.10191. PubMed PMID:12555269 .