The long-term goals of my research are to understand the cellular and molecular mechanisms of fertilization in eukaryotic cells. Our laboratory uses fertilization of the biflagellated alga Chlamydomonas as a model system. Chlamydomonas gametes of opposite sexes (mt+ and mt-) are endowed with adhesion and signal transduction molecules in their flagella. When mt+ and mt- gametes are mixed together they adhere to each other by their flagella adhesion molecules, thereby a signaling pathway within the flagella that ultimately triggers cellular responses that render the gametes able to fuse to form a zygote (the equivalent of a fertilized egg in multicellular organisms).
Because of discoveries in Chlamydomonas, we now appreciate that almost every cell in our body possesses a cilium (the primary cilium; cilia and flagella are equivalent organelles) that serves as an organizing center for detecting and responding to extracellular cues. Many important developmental and homeostatic processes in vertebrates depend on cilium-generated signaling, including the Sonic Hedgehog pathway, regulation of proliferation and organization of epithelial cells, and regulation of body weight.
At present, three research problems are under investigation in my laboratory.
Cilium-generated signaling: Recently we showed that the intraflagellar transport (IFT) machinery, which all cells use to assemble and maintain their cilia and flagella, is also essential for signaling within flagella. We are taking advantage of the ease of carrying out molecular biological, biochemical, and genetic studies in Chlamydomonas to dissect the molecular relationships between the IFT machinery and the components of the flagellar-adhesion induced signaling pathway.
Ciliary/flagellar shortening: Our studies have established that a Chlamydomonas member of the aurora family of protein kinases is an effector in a pathway for regulated flagellar disassembly, that the IFT machinery is regulated during flagellar shortening, and that a depolymerizing kinesin (Kinesin 13) is essential for flagellar length control and for flagellar shortening in Chlamydomonas. We are studying the interactions between the protein kinase, IFT components, and kinesin 13 to develop a coherent understanding of regulation of flagellar shortening.
Cell-cell fusion (and malaria transmission): Our recent studies on fusion of Chlamydomonas mt+ and mt- gametes has uncovered the broadly conserved principle that species-specific adhesion of fusogenic gamete membranes is governed by species-specific proteins, whereas the membrane fusion event that follows membrane adhesion is accomplished by a broadly conserved protein, HAP2. In a collaborative project with UK malaria researchers Robert Sinden and Oliver Billker we showed that HAP2 also is essential for mosquito transmission of malaria, and HAP2 has become a prime candidate for a transmission blocking vaccine. Currently, we are carrying out a molecular analysis of the functional domains of FUS1 (the species-specific membrane adhesion protein), and HAP2 (the protein essential for membrane fusion) and we are searching for their potential binding partners.
RESEARCH INTERESTS
The biology of cilia and flagella
Cilium-generated signaling and intraflagellar transport
Cellular and molecular mechanisms of cell-cell fusion
Malaria vaccines
RECENT PUBLICATIONS
Cole, D. and Snell, W. J., "SnapShot: Intraflagellar Transport" Cell, 137:784, 2009
Piao, T., Luo, M.W., L., Guo, Y., Li, D., Li, P., Snell, W.J., and Pan, J., "A microtubule depolymerizing kinesin functions during both flagellar disassembly and flagellar assembly in Chlamydomonas" Proceedings of the National Academy of Sciences, 106:4713-4718, 2009
Liu, Y., Tewari, R., Ning, J. Blagborough, A. M., Garbom, S., Pei, J., Grishin, N. V., Steele, Sinden, R. E., Snell, W. J., and Billker, O., "The conserved plant sterility gene HAP2 functions after attachment of fusogenic membranes in Chlamydomonas and Plasmodium gametes" Genes and Development, 22:1051-1068, 2008
Wang, Q, Pan, J, and, Snell W. J., "Intraflagellar transport particles participate directly in cilium-generated signaling in Chlamydomonas." Cell, 125:549-562, 2006
Pan, J. and Snell, W. J., "Chlamydomonas shortens its flagella by activating axonemal disassembly, stimulating IFT particle trafficking, and blocking anterograde cargo loading." Developmental Cell, Volume 9:431-438, 2004
SIGNIFICANT PUBLICATIONS
Pan, J., Wang, Q., and Snell, W. J., "An aurora kinase is essential for flagellar disassembly in Chlamydomonas" Developmental Cell, 6:445-451, 2004
Wang, Q. and W. J. Snell, "Flagellar adhesion between mating type plus and mating type minus gametes activates a flagellar protein tyrosine kinase during fertilization in Chlamydomonas" Journal of Biological Chemistry, 278:32936-32942, 2003
Misamore, M., Gupta, S. and Snell, W. J. 2003., "The Chlamydomonas mt+ gamete Fus1 protein is present on the mating type plus fertilization tubule and required for a critical membrane adhesion event during fusion with minus gametes" Molecular Biology of the Cell, 14:2530-2542, 2003
Pan, J. and Snell, W.J., "Kinesin II is required for flagellar sensory transduction during fertilization in Chlamydomonas." Molecular Biology of the Cell, 13:1417-1426, 2002
Snell, W.J., Dentler, W.L., Haimo, L.T., Binder, L.I., and Rosenbaum, J.L., "Assembly of chick brain tubulin onto isolated basal bodies of Chlamydomonas reinhardi." Science, 185:357-360, 1974
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