Michael J. Werle, PhD

Associate Professor
Associate Dean for Graduate Studies
Ph.D.: 1988, University of Southern California
Postdoctoral: Stanford University School of Medicine

The main focus of our research is directed toward understanding the cellular and molecular mechanism that control synapse formation, stabilization, elimination and remodeling. The model synapse that we study is the neuromuscular junction. In particular, we are interested in the cellular mechanisms that control the distribution of synapse specific molecules at the neuromuscular junction. One such molecule is the protein agrin. Agrin is a heparan sulfate proteoglycan. Agrin binds to synaptic basal lamina, and interacts with its receptor on the muscle fiber membrane to induce the formation of the postsynaptic apparatus. Since agrin plays a central role in the formation of the neuromuscular junction, it is likely that agrin will play a role in synapse elimination and synaptic remodeling. Experiments performed in this laboratory have revealed that agrin is quickly removed from synaptic basal lamina during normal synaptic retraction in adult frogs. During reinnervation agrin is completely removed from abandoned synaptic sites in which synaptic activity is present, while in contralateral control muscle that are inactive, agrin will remain bound to synaptic basal lamina. Decreasing synaptic activity during reinnervation delays the removal of agrin from synaptic basal lamina. These results are consistent with the hypothesis that synaptic activity controls a cellular mechanism that directs the removal of agrin from synaptic basal lamina. We hypothesize that synaptic activity causes the release or activation of proteases that cleave agrin from synaptic basal lamina.

Recent Publications

1. Werle, M.J., and Sojka, A.M. (1996) Anti-agrin staining is absent in empty gutters of frog neuromuscular junctions. J. Neurobiol. 30:293-302.
2. Stanco, A.M. and Werle, M.J. (1997) Agrin and acetylcholine receptors are removed from abandoned synaptic sites at reinnervated frog neuromuscular junctions. J. Neurobiol. 33:999-1018.
3. Werle, M.J., Roder, J., and Jeromin, A. (2000) Expression of frequenin at the frog (Rana) neuromuscular junction. Neuroscience Letts. 284:33-36.
4. Jones, M.A. and Werle, M.J. (2000) Nitric Oxide is a downstream mediator of agrin induced acetylcholine receptor aggregation. Molecular and Cellular Neuroscience: 16:649-660.
5. Jones, M.A. and Werle, M.J. (2004) Agrin induced AChR aggregate formation requires cGMP and aggregate maturation requires activation of cGMP-dependent protein kinase. Molecular and Cellular Neuroscience 25(2):195-204.
6. VanSaun, M. and Werle, M.J. (2000) Matrix metalloproteinase-3 removes agrin from synaptic basal lamina. J. Neurobiol. 43:140-149.
7. VanSaun, M., Herrera, A.A. and Werle, M.J. (2003) Structural Alterations at the Neuromuscular Junctions of Matrix Metalloproteinase 3 Null Mutant Mice. J. Neurocytology 32(9):1129-42.
8. Werle, M.J. and VanSaun, M. (2003) Activity Dependent Removal Of Agrin From Synaptic Basal Lamina By Matrix Metalloproteinase 3. J. Neurocytol. 32(5-8):905-13.
9. Rodova, M., Kelly, K.F., VanSaun, M., Daniel, J.M., and Werle, M.J. (2004) Regulation of the rapsyn promoter by Kaiso and -catenin at the neuromuscular junction. Molecular and Cellular Biology. In press.
10. Rodova, M., and Werle, M.J. (2004) Okadaic acid augments utrophin in myogenic cells. Neuroscience Letters. In press.

Former Trainees

• Anne Stanco, Ph.D.
• Melissa Jones, Ph.D. Postdoctoral Fellow
• Michael VanSaun, Ph.D. Postdoctoral Fellow

Left to right: Marianna Rodova (Postdoctoral Fellow), Mike Werle (PI),
Ashley Burdex (Undergraduate Summer Research)