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Dr.
Susan Cumberledge Signal transduction at the neuromuscular junction and regulation of synaptogenesis susanc@biochem.umass.edu
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| Background and Training | ||
| Ph.D.: University of California
at Santa Barbara |
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| Research Summary | ||
| Our lab studies how cell-cell communication regulates synaptogenesis at the Drosophila neuromuscular junction. Drosophila, with its sophisticated genetic, biochemical and developmental tools is an ideal model system for studying both synaptogenesis and synaptic remodeling during growth and neuronal injury. Previous studies in our lab demonstrated that motorneurons secrete Wnt-1. Moreover, this Wnt signaling regulates the assembly of new synapses, as well as growth of existing connections. While examining the post-synaptic muscle cells, we found that the Wnt-1 ligand triggers cleavage of the cell surface Frizzled-2 receptor and transport of the C-terminal receptor fragment into the muscle nucleus. These findings indicate that Wnt-1 signaling at the neuromuscular junction occurs via a novel Wnt signaling pathway. We are currently defining the steps in this novel pathway. Much of our current work concerns the role of Arrow, a member of the low density lipoprotein related receptor family.
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 As
the adult visual system develops, a complex neural network is created.
This network links photoreceptors of the eye with the appropriate central
neurons. Wingless expression in developing brain provides important positional
cues for incoming photoreceptor axons. Arrow denotes dorsal-ventral border.
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A second area of study in the lab focuses on the interplay between Wnt signaling and the activity of Amyloid Precursor Like Protein (APPL) during synaptogenesis. APPL is the Drosophila homolog of human APP, a secreted protein tightly associated with Alzheimer’s disease. We are examining both the role of APPL during synaptogenesis under normal and stress conditions and how Wnt signaling components regulate APPL trafficking at the neuromuscular junction.
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| Representative Publications | ||
Mathew D, Ataman B, Chen J, Zhang Y, Cumberledge S, Budnik V. (2005) Wingless signaling at synapses is through cleavage and nuclear import of receptor DFrizzled2. Science 310:1344-7. Comment in Science. 2005 310: 1284-5. Zhai,L., Chaturvedi, D., & S. Cumberledge. (2004) Drosophila Wnt-1 undergoes a hydrophobic modification and is targeted to lipid rafts; a process that requires Porcupine. J Biol Chem. 279: 33220-7. Packard, M. Koo, S., Gorczyca, M., Sharpe, J., Cumberledge,S., and V. Budnik (2002) The Drosophila Wnt1 homolog, Wingless, provides an essential signal for pre- and post synaptic differentiation. Cell 111: 319-30. Alexander, C.M., Reichsman, F., Hinkes, M.T., Lincecum, J., Becker, J., Cumberledge, S, and M. Bernfield (2000) Syndecan-1 is Required for Wnt-1-induced Mammary Tumorigenesis in Mice. Nature Genetics 25:329-32. Uren, A., Reichsman, F. Cumberledge, S. and J.S. Rubin (2000) Secreted Frizzled Related Protein (sFRP-1) binds directly to Wingless and is a biphasic modulator of Wnt signaling. Journal of Biological Chemistry, 275(6): 4374-82. Reichsman, F., Moore, H. and S. Cumberledge (1999) Sequence homology between Wingless/Wnt-1 and a lipid-binding domain in secreted phospholipase A2. Current Biology 20: 353-5. Cumberledge, S. and F. Reichsman (1997) Glycosaminoglycans and Wnts. Trends in Genetics 13: 221-25. Reichsman, F., Smith, L. and S. Cumberledge (1996) Glycosaminoglycans Can Mediate Extracellular Localization of the wingless Protein and Promote Signal Transduction. Journal of Cell Biology 135: 819-27. |
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