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 have 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.