James C. ClemensAssistant Professor of Biochemistry Area: Molecular mechanisms of neuron connection specificity |
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Specialized cells called neurons are the basic components of animal nervous systems. Similar to electrical wires, neurons link together to form circuits through specialized membrane contact points know as synapses. These circuits are further assembled into ordered networks that cooperate with each other to ultimately form a functioning nervous system. What is truly remarkable about this process is the sheer complexity of neuronal connectivity. For example it is estimated that the human brain contains a trillion neurons that are networked via a quadrillion synaptic connections.
How neurons discriminate between potential synaptic partners to form specific connections presents a complex problem of molecular recognition between cell surface proteins displayed upon opposing cell surfaces. These proteins and the molecular mechanisms underlying this process are the focus of our research. We use the Drosophila melanogaster brain as an experimental model system and address the issue of connection specificity using a combination of genetic, molecular, and biochemical approaches.
Central to our current studies is a cell surface receptor called Down syndrome cell adhesion molecule (Dscam). Dscam is a member of the Immunoglobulin super-family and plays a widespread role in connection fidelity throughout the fly nervous system. Remarkably, the single Dscam gene can produce as many as 38,016 different protein isoforms that exhibit isoform specific homophilic interactions. Our current studies address how Dscam diversity contributes to connection specificity, Dscam signaling mechanisms, and the influence of Dscam activity on other guidance receptor systems.
Selected Publications:
- Mathews, B.J., M.E. Kim, J.J. Flanagan, D. Hattori, J.C. Clemens, S.L. Zipursky and W.B. Grueber. Dendrite self-avoidance is controlled by Dscam. Cell 129: 593-604 (2007).
- Zhu H., Hummel T., Clemens J.C., Berdnik D., Zipursky L. and Luo L. Dendritic patterning by Dscam and synaptic partner matching in the Drosophila antennal lobe. Nat. Neurosci. 9: 349-355 (2006).
- Graveley B.R., Kaur A., Gunning D., Zipursky S.L., Rowen L. and Clemens J.C. The organization and evolution of the Dipteran and Hymenopteran Down syndrome cell adhesion molecule (Dscam) genes. RNA 10: 1499-1506 (2004).
- Wojtowicz W.M., Flanagan J.J., Millard S.S., Zipursky S.L. and Clemens J.C. Alternative splicing of Drosophila Dscam generates axon guidance receptors that exhibit isoform-specific homophilic binding. Cell 118: 619-633 (2004).
- Zhan X.L., Clemens J.C., Neves G., Hattori D., Flanagan J.J., Hummel T., Vasconcelos M.L., Chess A. and Zipursky S.L. Analysis of Dscam diversity in regulating axon guidance in Drosophila mushroom bodies. Neuron 43: 673-686 (2004).
- Hummel T., Vasconcelos M.L., Clemens J.C., Fishilevich Y., Vosshall L.B. and Zipursky S.L. Axonal Targeting of Olfactory Receptor Neurons in Drosophila is Controlled by Dscam. Neuron 37: 221-231 (2003).
- Muda M., Worby C.A. , Simonson-Leff N., Clemens J.C. and Dixon J.E. Use of Double-Stranded RNA Mediated Interference to Determine the Substrates of Protein Tyrosine Kinases and Phosphatases. Biochem. J. 366: 73-77 (2002).
- Schmucker D.*, Clemens J.C.*, Shu H.*, Worby C.A. , Xiao J., Muda M., Dixon J.E. and Zipursky S.L. Drosophila Dscam is an axon guidance receptor exhibiting extraordinary molecular diversity. Cell 101: 671-684 (2000).
