assembly of cell organelles using the flagella of Chlamydomonas as a model
Joel Rosenbaum, Ph.D.

Joel Rosenbaum, Ph.D.

Professor of Molecular, Cellular & Developmental Biology
Room: KBT 310A
Phone: (203) 432-3472/ (203) 432-3473
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B.S. Syracuse University 1955; M.Sc. Ed. St. Lawrence University 1957; M.S. Syracuse University 1959; Ph.D. Syracuse University 1963

We are using the flagella of the bi-flagellate alga Chlamydomonas as a model system for studying the assembly of cell organelles. Detachment of the flagella induces the rapid and coordinate synthesis of tubulin and over 200 other flagellar mRNAs, the synthesis of flagellar proteins in the cytoplasm and their ultimate assembly in the flagellum, which is regenerated in about an hour. Chlamydomonas, which has been called the "green yeast", is an ideal cell for these studies as its genetics are well-developed and, like yeast, it is haploid, mates, and produces meiotic spores whose tetrads can be separated and analyzed. Chlamydomonas cell division is easily synchronized; it can be inexpensively cultured in large quantities, and it can be transformed with exogenous DNA by simple procedures.

We have described a new motility in the flagellum called "IFT" (for Intraflagellar Transport). IFT is the kinesin and cytoplasmic dynein-dependent bi-directional movement of large protein particles, underneath the flagellar membrane, associated with the B-tubules of the outer doublets of the axoneme. IFT is essential for both the assembly and maintenance of the flagellum. Mutants have been obtained in both the anterograde (kinesin-dependent) and retrograde (cytoplasmic dynein-dependent) movement of the IFT particles. This motility represents the only microtubule-based motility system in Cell Biology in which mutants are available in both directions and in which the cargo can be isolated and analyzed. The IFT particles are composed of ca. 17 polypeptides which have homologues in Caenorhabditis elegans. Mutants in the genes for these polypeptides in C elegans result in defects in the assembly of cilia-containing sensory neurons. The same kinesin found to be important for IFT particle motility and motile flagellar assembly and for C. elegans sensory cilia assembly, is also found in the connecting cilium between vertebrate rod inner and outer segments of the retina. Therefore, this flagellar motility process is required for the assembly and maintenance of all motile cilia and flagella, as well as for non-motile sensory cilia. Exactly how the IFT particles are functioning to move flagellar precursors into (and out of) the ciliary and flagellar assembly sites is a major project under investigation in our laboratory.
Since the flagella assemble at their tip we are interested in how the flagellar proteins are targeted to the flagellar compartment; what state of assembly they are in before entering the flagellum (are there pre-assembly complexes?); how they are transported to the flagellar tip; and how unloading of cargo and reversal of IFT is controlled at the flagellar tip. We have obtained evidence that the flagellar radial spokes, containing 23 polypeptides, are pre-assembled in the cytoplasm prior to transfer into the flagellar compartment. This very large preassembly complex is then transported to the flagellar tip for assembly onto the microtubules by IFT. Using IFT mutants we have begun to dissect the mechanism used to unload cargo at the tip and rearrange IFT particles for their return to the cell body.

More recently our interests have broadened to include sensory function of cilia and flagella and their relationship to the cell cycle. We have found that one of the IFT proteins, IFT27, is important, not only in flagellar assembly but also in regulating the cell cycle. Depleting IFT27 by RNAi can cause the cell cycle to become stalled, to block cytokinesis, or even to result in cell death. We are currently exploring this link between cilia/flagella and the cell cycle.  The connection between cilia and the cell cycle is dramatically illustrated in polycystic kidney disease (PKD), the most common genetic disease leading to kidney failure. In the absence of cilia in the kidney tubules, cells lining the tubules begin to divide unrestrained, forming cysts that compromise kidney function. The link between kidney cilia and the cell division depends on two proteins called polycystin-1 and -2. These proteins form mechanosensitive calcium channels in the cilia that can regulate cell division. We have begun to study the properties of one of these proteins, PKD2, in the flagella of Chlamydomonas and found that it is involved in generating a calcium influx that initiates the mating reaction in these cells. Mating of Chlamydomonas should be, therefore, a convenient method for screening for drugs that affect PKD2 activity as well as compounds that affect the many sensory signaling pathways common to cilia and flagella.

Selected Publications

Kozminski, K. G., P. L. Beech, and J. L. Rosenbaum. 1995. The Chlamydomonas kinesin-like protein FLA10 is involved in motility associated with the flagellar membrane. J. Cell Biol. 131:1517-27.

Cole, D. G., D. R. Diener, A. L. Himelblau, P. L. Beech, J. C. Fuster, and J. L. Rosenbaum. 1998. Chlamydomonas kinesin-II-dependent intraflagellar transport (IFT): IFT particles contain proteins required for ciliary assembly in Caenorhabditis elegans sensory neurons. J. Cell Biol. 141:993-1008.

Marshall, W. F., and J. L. Rosenbaum. 2001. Intraflagellar transport balances continuous turnover of outer doublet microtubules: implications for flagellar length control. J. Cell Biol. 155:405-14.

Qin, H., D. Diener, S. Geimer, D. Cole, and J. Rosenbaum. 2004. Intraflagellar transport (IFT) cargo: IFT transports flagellar precursors to the tip and turnover products to the cell body. J. Cell Biol. 164:255-266.

Pedersen, L. B., S. Geimer, and J. L. Rosenbaum. 2006. Dissecting the molecular mechanisms of intraflagellar transport in Chlamydomonas. Current Biology. 16:450-459.

Qin, H., Z. Wang, D. Diener, and J. Rosenbaum. 2007. Intraflagellar transport protein 27 is a small G protein involved in cell-cycle control. Current Biology. 17:193-202.

Huang, K., D. Diener, A. Mitchell, G. J. Pazour, G. B. Witman, and J. L. Rosenbaum. 2007. Function and dynamics of PKD2 in Chlamydomonas flagella. J. Cell Biol. in press.



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