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Intracellular motility: A special delivery service
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Intracellular motility: A special delivery service William M. Saxton
Recent studies have identified a delivery service that operates in specialised cell appendages: two motor proteins and a novel protein organelle use axonemal microtubules as tracks to shuttle essential components to the tips of flagella and the dendrites of sensory neurons. Address: Department of Biology, Indiana University, Bloomington, Indiana 47465, USA. Current Biology 1999, 9:R293–R295 http://biomednet.com/elecref/09609822009R0293 © Elsevier Science Ltd ISSN 0960-9822
Intracellular transport processes in eukaryotes are used to solve molecular delivery problems caused by compartmentalization and complex cell shapes. Force-generating ATPases that act as molecular motors attach to organelles or other cytoplasmic cargoes and pull them along filamentous polymers: microfilaments composed of actin or microtubules composed of tubulin. These filaments have an intrinsic structural polarity; that is, the subunits are asymmetric and they polymerize head-to-tail. Individual motor proteins recognize this polarity and move specifically in one direction or the other. By controlling filament distribution, motor–cargo interactions and motor–filament interactions, eukaryotic cells are able to solve a great variety of delivery problems. A dramatic example of the need for such active transport processes is provided by the eukaryotic flagellum. This structure forms as a long, narrow extension of the plasma membrane draped around an ‘axoneme’, a beautifully ordered array of microtubules with their ‘minus ends’ close to the cell body and their ‘plus ends’ away from the cell body. A variety of proteins associate with or crosslink the axonemal microtubules, including the flagellar dyneins that provide force for the rhythmic axoneme bending that powers flagellar beating [1]. During normal growth of a flagellum, the tubulin and most other subunits of the axoneme are added near the tip [2,3]. In the tight confines of a flagellum, which is approximately 0.3 µm wide, the lengthwise movement of macromolecules by simple diffusion must be quite slow, and certainly insufficient to move protein assemblies from their sites of synthesis in the cell body to a rapidly growing axoneme tip that can be hundreds of microns distant. A newly discovered form of active transport operates within the flagella of Chlamydomonas, a single-celled alga [4]. Several years ago, Kozminski et al. [5] observed this intraflagellar transport by scrutinizing paralyzed flagellar
mutants with a video-enhanced light microscope. What appeared to be refractile lumps in the flagellar membrane were seen to move longitudinally within a flagellum, larger lumps moving from the base toward tip at about 2 µm per second (anterograde movement), and smaller ones moving from the tip toward base at 3.5 µm per second (retrograde movement). Electron microscopy suggested that the moving objects, or ‘rafts’, are chains of lollipop-shaped osmiophilic particles that lie along the B-tubules of the outer doublet microtubules, connecting them to the flagellar membrane (Figure 1). The rafts were seen to vary in length, containing from a few to more than 40 of the particles. Might the movement of rafts be the means by which axoneme subunits move to the tip of the flagellum? Recent studies of Chlamydomonas flagellar assembly (FLA) mutants have provided evidence that rafts and their transport are indeed linked to axoneme assembly [6–8]. A conditional mutation of the FLA10 gene, fla10-1 was found at the restrictive temperature to cause gradual resorption of existing flagella and prevent regrowth [9]. Kozminski et al. [8] observed further that fla10-1 causes the loss of intraflagellar transport in both directions and a dramatic depletion of rafts from flagella. The FLA10 gene was found to encode a microtubule motor protein [10], specifically a member of the heteromeric kinesin subfamily that acts as a ‘plus-end-directed’ motor — that is, it moves along a microtubule from the minus to the plus end. Immunoelectron microscopy indicated that, in the flagellum, the Fla10 protein is concentrated between the membrane and the outer doublet microtubules, the space which also contains intraflagellar transport rafts [8]. This suggests that rafts are transported along B-tubules toward the tip of the flagellum by a Fla10-heteromeric kinesin, and that without such active transport, axonemes can neither grow nor be maintained. What of retrograde intraflagellar transport? One would expect that intraflagellar transport particles are moved from tip toward base by a minus-end-directed microtubule motor, either a cytoplasmic dynein or a member of the carboxy-terminal kinesin subfamily. Pazour et al. [7] observed that deletion of the Chlamydomonas FLA14 gene blocked retrograde, but not anterograde, intraflagellar transport. This one-way movement led to the mutant cells having short flagella with distended tips that were filled with rafts. FLA14 encodes LC8, a cytoplasmic dynein light chain, suggesting that cytoplasmic dynein is the primary motor for retrograde intraflagellar transport. This hypothesis has received support from the recent observation that
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Current Biology, Vol 9 No 8
Figure 1 (a)
Intraflagellar transport rafts in a flagellum. (a) A cross-sectional view of a flagellum, with intraflagellar transport raft particles positioned between the B-tubules of the outer doublets and the plasma membrane. (b) A longitudinal view of a flagellum, highlighting the directions of raft movement and potential motor–raft associations.
(b)
To axoneme tip (anterograde)
Membrane Microtubule Radial spokes Flagellar dyneins Raft particle FLA10-kinesin Cytoplasmic dynein
To cell body (retrograde)
0.1 µm Current Biology
similar defects — stumpy flagella filled with raft components — are caused by mutation of the gene STF1/DHC1b, which encodes dynein heavy chain 1b [11,12]. The FLA14 and STF1/DHC1b mutant phenotypes indicate that retrograde intraflagellar transport is critical for axoneme growth and maintenance, and confirm that rafts are indeed the previously observed intraflagellar transport ‘lumps’. What are the rafts made of? By combining Chlamydomonas genetics with meticulous biochemistry, Cole et al. [6] have isolated and characterized two raft complexes. By tracing a number of proteins that were depleted from fla10-1 flagella at restrictive temperature, Cole et al. [6] fractionated wild-type flagella and isolated two approximately 16S particles: complex A, containing four polypeptides, and complex B, containing eleven polypeptides. Piperno and Mead [13] discovered what is apparently the same particle, and reported a weak association with the flagellar dynein subunit p28(IDA4). Three lines of evidence argue that the A and B complexes isolated by Cole et al. [6] are indeed raft components. First, the amounts of A and B polypeptides correlate with the abundance of rafts; they are greatly reduced by fla10-1 and are dramatically increased by FLA14 and STF1/DHC1b mutations. Second, immunofluorescence labelling with antibodies specific for the A complex, the B complex, Fla10 or DHC1b revealed punctate concentrations of those proteins along the lengths of flagella, the distribution expected for raft components [6,7,11,12]. And third, small but consistently detectable amounts of Fla10 co-fractionate with complex A during rapid immunoprecipitation [6]. This raises the possibility of a direct, albeit perhaps weak, association between a complex A component and a
known intraflagellar transport motor. Certainly the issue of how motors and rafts interact physically is critical and demands further investigation. The preliminary characterization of the major proteins of complexes A and B by microsequencing has revealed that intraflagellar transport is an ancient process [6,7]. The complex B polypeptide p52 turns out to be a homologue of the Caenorhabditis elegans protein OSM-6. OSM-6 is present in ciliated sensory neurons of C. elegans, and osm-6 mutations disrupt ciliary axoneme assembly in those neurons. Together, these observations argue that raft components and functions are shared by C. elegans and Chlamydomonas. Sensory neuron axonemes in C. elegans are also disrupted by osm-1, osm-3 and che-3 mutations, which encode homologues of p172 (a complex B component), Fla10 and a cytoplasmic dynein heavy chain, respectively [6,7]. It is striking that the che-3 mutation causes short sensory cilia that are swollen with both osmiophilic material and OSM-6 protein, quite reminiscent of the raft pile-ups caused by FLA14 or STF1/DHC1b mutations in Chlamydomonas [14,15]. It is apparent that rafts and intraflagellar transport evolved before the divergence of algae and animals. Are there signs that intraflagellar transport is important in animals other than C. elegans? The answer seems to be yes; for example, when antibodies that inhibit the Fla10related kinesin KRP85 were injected into one cell of a sea urchin embryo, the growth of cilia from that cell was inhibited [16]. Targeted mutation in mice of the gene for KIF3B, another Fla10-related kinesin, led to a failure of nodal cells to assemble cilia, and embryonic death [17]. Immunolocalization has suggested that, in the fish retina,
Dispatch
a Fla10 homologue is concentrated around the axoneme in the cilium that connects the inner and outer segments of photoreceptors [18]. And as reported at the recent meeting of the American Society for Cell Biology (San Francisco, December 12–16, 1998), tissue-specific disruption of the gene for the Fla10-related kinesin KIF3A in mouse photoreceptors led to deterioration of the photoreceptor outer segments [19]. Direct visualization of rafts in vertebrates has not been reported yet, but NGD5, a homologue of the Chlamydomonas raft protein p52, has been found to be present in rat neural tissue [20]. In view of these observations, it is reasonable to expect that intraflagellar transport and rafts will be found to be widespread and important in higher animals. Recent studies of intraflagellar transport have thus provided exciting insights into mechanisms of flagellar assembly and the role of axonemes in sensory neurons. Intraflagellar transport also provides a potentially powerful new system for studying microtubule-based motility: it is a perfectly linear and polar transport process, primary anterograde and retrograde motors have been identified and a specific cargo complex has been purified. Furthermore, intraflagellar transport and rafts can be studied in two excellent genetic systems, one (C. elegans) with a completely sequenced genome. Little is known about the physical relationship between microtubule motors and their cargoes in any transport processes, and answers to questions about intraflagellar transport should help fill that gap. How do motor proteins bind to rafts? And what is the relationship between rafts and axoneme subunits? Perhaps components such as tubulin and flagellar dynein associate directly with the A and B complexes and are carried as resolute cargoes [13]. At the other extreme, there might be no direct association: rafts might act as simple impellers, displacing cytosol along the narrow space between the outer doublets and plasma membrane, thereby facilitating the diffusion of axoneme subunits. Whatever the truth turns out to be, real answers to questions about both motor–cargo relationships and the movement of materials along axonemes are on the horizon. Acknowledgements Support was provided by an Established Investigatorship from the American Heart Association with funds provided in part by the AHA Indiana Affiliate Inc.
References 1. Dutcher SK: Flagellar assembly in two hundred and fifty easy-to-follow steps. Trends Genet 1995, 11:398-404. 2. Johnson KA, Rosenbaum JL: Polarity of flagellar assembly in Chlamydomonas. J Cell Biol 1992, 119:1605-1611. 3. Rosenbaum JL, Moulder JE, Ringo DL: Flagellar elongation and shortening in Chlamydomonas. The use of cycloheximide and colchicine to study the synthesis and assembly of flagellar proteins. J Cell Biol 1969, 41:600-619. 4. Rosenbaum JL, Cole DG, Diener DR: Intraflagellar transport: the eyes have it. J Cell Biol 1999, 144:385-388. 5. Kozminski KG, Johnson KA, Forscher P, Rosenbaum JL: A motility in the eukaryotic flagellum unrelated to flagellar beating. Proc Natl Acad Sci USA 1993, 90:5519-5523.
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6. Cole DG, Diener DR, Himelblau AL, Beech PL, Fuster JC, Rosenbaum JL: Chlamydomonas kinesin-II-dependent intraflagellar transport (IFT): IFT particles contain proteins required for ciliary assembly in Caenorhabditis elegans sensory neurons. J Cell Biol 1998, 141:993-1008. 7. Pazour GJ, Wilkerson CG, Witman GB: A dynein light chain is essential for the retrograde particle movement of intraflagellar transport (IFT). J Cell Biol 1998, 141:979-992. 8. Kozminski KG, Beech PL, Rosenbaum JL: The Chlamydomonas kinesin-like protein FLA10 is involved in motility associated with the flagellar membrane. J Cell Biol 1995, 131:1517-1527. 9. Lux III FG, Dutcher SK: Genetic interactions at the FLA10 locus: suppressors and synthetic phenotypes that affect the cell cycle and flagellar function in Chlamydomonas reinhardtii. Genetics 1991, 128:549-561. 10. Walther Z, Vashishtha M, Hall JL: The Chlamydomonas FLA10 gene encodes a novel kinesin-homologous protein. J Cell Biol 1994, 126:175-188. 11. Pazour GJ, Dickert BL, Witman GB: The DHC1b (DHC2) isoform of cytoplasmic dynein is required for flagellar assembly. J Cell Biol 1999, 144:473-481. 12. Porter ME, Bower R, Knott JA, Byrd P, Dentler WL: Cytoplasmic dynein heavy chain 1b is required for flagellar assembly in Chlamydomonas. Mol Biol Cell 1999, 10:693-712. 13. Piperno G, Mead K: Transport of a novel complex in the cytoplasmic matrix of Chlamydomonas flagella. Proc Natl Acad Sci USA 1997, 94:4457-4462. 14. Collet J, Spike CA, Lundquist EA, Shaw JE, Herman RK: Analysis of osm-6, a gene that affects sensory cilium structure and sensory neuron function in Caenorhabditis elegans. Genetics 1998, 148:187-200. 15. Lewis JA, Hodgkin JA: Specific neuroanatomical changes in chemosensory mutants of the nematode Caenorhabditis elegans. J Comp Neurol 1977, 172:489-510. 16. Morris RL, Scholey JM: Heterotrimeric kinesin-II is required for the assembly of motile 9+2 ciliary axonemes on sea urchin embryos. J Cell Biol 1997, 138:1009-1022. 17. Nonaka S, Tanaka Y, Okada Y, Takeda S, Harada A, Kanai Y, Kido N, Hirokawa N: Randomization of left-right asymmetry due to loss of nodal cilia generating leftward flow of extraembryonic fluid in mice lacking KIF3B motor protein. Cell 1998, 95:829-837. 18. Beech PL, Pagh-Roehl K, Noda Y, Hirokawa N, Burnside B, Rosenbaum JL: Localization of kinesin superfamily proteins to the connecting cilium of fish photoreceptors. J Cell Sci 1996, 109:889-897. 19. Marszalek JR, Liu X, Roberts E, Chui D, Marth J, Williams DS, Goldstein LB: Tissue specific deletion of KIF3A from photoreceptors results in their degeneration. Mol Biol Cell 1998, 9:131a. 20. Wick MJ, Ann DK, Loh HH: Molecular cloning of a novel protein regulated by opioid treatment of NG108-15 cells. Brain Res Mol Brain Res 1995, 32:171-175.
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Intracellular motility: A special delivery service William M. Saxton
Recent studies have identified a delivery service that operates in specialised cell appendages: two motor proteins and a novel protein organelle use axonemal microtubules as tracks to shuttle essential components to the tips of flagella and the dendrites of sensory neurons. Address: Department of Biology, Indiana University, Bloomington, Indiana 47465, USA. Current Biology 1999, 9:R293–R295 http://biomednet.com/elecref/09609822009R0293 © Elsevier Science Ltd ISSN 0960-9822
Intracellular transport processes in eukaryotes are used to solve molecular delivery problems caused by compartmentalization and complex cell shapes. Force-generating ATPases that act as molecular motors attach to organelles or other cytoplasmic cargoes and pull them along filamentous polymers: microfilaments composed of actin or microtubules composed of tubulin. These filaments have an intrinsic structural polarity; that is, the subunits are asymmetric and they polymerize head-to-tail. Individual motor proteins recognize this polarity and move specifically in one direction or the other. By controlling filament distribution, motor–cargo interactions and motor–filament interactions, eukaryotic cells are able to solve a great variety of delivery problems. A dramatic example of the need for such active transport processes is provided by the eukaryotic flagellum. This structure forms as a long, narrow extension of the plasma membrane draped around an ‘axoneme’, a beautifully ordered array of microtubules with their ‘minus ends’ close to the cell body and their ‘plus ends’ away from the cell body. A variety of proteins associate with or crosslink the axonemal microtubules, including the flagellar dyneins that provide force for the rhythmic axoneme bending that powers flagellar beating [1]. During normal growth of a flagellum, the tubulin and most other subunits of the axoneme are added near the tip [2,3]. In the tight confines of a flagellum, which is approximately 0.3 µm wide, the lengthwise movement of macromolecules by simple diffusion must be quite slow, and certainly insufficient to move protein assemblies from their sites of synthesis in the cell body to a rapidly growing axoneme tip that can be hundreds of microns distant. A newly discovered form of active transport operates within the flagella of Chlamydomonas, a single-celled alga [4]. Several years ago, Kozminski et al. [5] observed this intraflagellar transport by scrutinizing paralyzed flagellar
mutants with a video-enhanced light microscope. What appeared to be refractile lumps in the flagellar membrane were seen to move longitudinally within a flagellum, larger lumps moving from the base toward tip at about 2 µm per second (anterograde movement), and smaller ones moving from the tip toward base at 3.5 µm per second (retrograde movement). Electron microscopy suggested that the moving objects, or ‘rafts’, are chains of lollipop-shaped osmiophilic particles that lie along the B-tubules of the outer doublet microtubules, connecting them to the flagellar membrane (Figure 1). The rafts were seen to vary in length, containing from a few to more than 40 of the particles. Might the movement of rafts be the means by which axoneme subunits move to the tip of the flagellum? Recent studies of Chlamydomonas flagellar assembly (FLA) mutants have provided evidence that rafts and their transport are indeed linked to axoneme assembly [6–8]. A conditional mutation of the FLA10 gene, fla10-1 was found at the restrictive temperature to cause gradual resorption of existing flagella and prevent regrowth [9]. Kozminski et al. [8] observed further that fla10-1 causes the loss of intraflagellar transport in both directions and a dramatic depletion of rafts from flagella. The FLA10 gene was found to encode a microtubule motor protein [10], specifically a member of the heteromeric kinesin subfamily that acts as a ‘plus-end-directed’ motor — that is, it moves along a microtubule from the minus to the plus end. Immunoelectron microscopy indicated that, in the flagellum, the Fla10 protein is concentrated between the membrane and the outer doublet microtubules, the space which also contains intraflagellar transport rafts [8]. This suggests that rafts are transported along B-tubules toward the tip of the flagellum by a Fla10-heteromeric kinesin, and that without such active transport, axonemes can neither grow nor be maintained. What of retrograde intraflagellar transport? One would expect that intraflagellar transport particles are moved from tip toward base by a minus-end-directed microtubule motor, either a cytoplasmic dynein or a member of the carboxy-terminal kinesin subfamily. Pazour et al. [7] observed that deletion of the Chlamydomonas FLA14 gene blocked retrograde, but not anterograde, intraflagellar transport. This one-way movement led to the mutant cells having short flagella with distended tips that were filled with rafts. FLA14 encodes LC8, a cytoplasmic dynein light chain, suggesting that cytoplasmic dynein is the primary motor for retrograde intraflagellar transport. This hypothesis has received support from the recent observation that
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Current Biology, Vol 9 No 8
Figure 1 (a)
Intraflagellar transport rafts in a flagellum. (a) A cross-sectional view of a flagellum, with intraflagellar transport raft particles positioned between the B-tubules of the outer doublets and the plasma membrane. (b) A longitudinal view of a flagellum, highlighting the directions of raft movement and potential motor–raft associations.
(b)
To axoneme tip (anterograde)
Membrane Microtubule Radial spokes Flagellar dyneins Raft particle FLA10-kinesin Cytoplasmic dynein
To cell body (retrograde)
0.1 µm Current Biology
similar defects — stumpy flagella filled with raft components — are caused by mutation of the gene STF1/DHC1b, which encodes dynein heavy chain 1b [11,12]. The FLA14 and STF1/DHC1b mutant phenotypes indicate that retrograde intraflagellar transport is critical for axoneme growth and maintenance, and confirm that rafts are indeed the previously observed intraflagellar transport ‘lumps’. What are the rafts made of? By combining Chlamydomonas genetics with meticulous biochemistry, Cole et al. [6] have isolated and characterized two raft complexes. By tracing a number of proteins that were depleted from fla10-1 flagella at restrictive temperature, Cole et al. [6] fractionated wild-type flagella and isolated two approximately 16S particles: complex A, containing four polypeptides, and complex B, containing eleven polypeptides. Piperno and Mead [13] discovered what is apparently the same particle, and reported a weak association with the flagellar dynein subunit p28(IDA4). Three lines of evidence argue that the A and B complexes isolated by Cole et al. [6] are indeed raft components. First, the amounts of A and B polypeptides correlate with the abundance of rafts; they are greatly reduced by fla10-1 and are dramatically increased by FLA14 and STF1/DHC1b mutations. Second, immunofluorescence labelling with antibodies specific for the A complex, the B complex, Fla10 or DHC1b revealed punctate concentrations of those proteins along the lengths of flagella, the distribution expected for raft components [6,7,11,12]. And third, small but consistently detectable amounts of Fla10 co-fractionate with complex A during rapid immunoprecipitation [6]. This raises the possibility of a direct, albeit perhaps weak, association between a complex A component and a
known intraflagellar transport motor. Certainly the issue of how motors and rafts interact physically is critical and demands further investigation. The preliminary characterization of the major proteins of complexes A and B by microsequencing has revealed that intraflagellar transport is an ancient process [6,7]. The complex B polypeptide p52 turns out to be a homologue of the Caenorhabditis elegans protein OSM-6. OSM-6 is present in ciliated sensory neurons of C. elegans, and osm-6 mutations disrupt ciliary axoneme assembly in those neurons. Together, these observations argue that raft components and functions are shared by C. elegans and Chlamydomonas. Sensory neuron axonemes in C. elegans are also disrupted by osm-1, osm-3 and che-3 mutations, which encode homologues of p172 (a complex B component), Fla10 and a cytoplasmic dynein heavy chain, respectively [6,7]. It is striking that the che-3 mutation causes short sensory cilia that are swollen with both osmiophilic material and OSM-6 protein, quite reminiscent of the raft pile-ups caused by FLA14 or STF1/DHC1b mutations in Chlamydomonas [14,15]. It is apparent that rafts and intraflagellar transport evolved before the divergence of algae and animals. Are there signs that intraflagellar transport is important in animals other than C. elegans? The answer seems to be yes; for example, when antibodies that inhibit the Fla10related kinesin KRP85 were injected into one cell of a sea urchin embryo, the growth of cilia from that cell was inhibited [16]. Targeted mutation in mice of the gene for KIF3B, another Fla10-related kinesin, led to a failure of nodal cells to assemble cilia, and embryonic death [17]. Immunolocalization has suggested that, in the fish retina,
Dispatch
a Fla10 homologue is concentrated around the axoneme in the cilium that connects the inner and outer segments of photoreceptors [18]. And as reported at the recent meeting of the American Society for Cell Biology (San Francisco, December 12–16, 1998), tissue-specific disruption of the gene for the Fla10-related kinesin KIF3A in mouse photoreceptors led to deterioration of the photoreceptor outer segments [19]. Direct visualization of rafts in vertebrates has not been reported yet, but NGD5, a homologue of the Chlamydomonas raft protein p52, has been found to be present in rat neural tissue [20]. In view of these observations, it is reasonable to expect that intraflagellar transport and rafts will be found to be widespread and important in higher animals. Recent studies of intraflagellar transport have thus provided exciting insights into mechanisms of flagellar assembly and the role of axonemes in sensory neurons. Intraflagellar transport also provides a potentially powerful new system for studying microtubule-based motility: it is a perfectly linear and polar transport process, primary anterograde and retrograde motors have been identified and a specific cargo complex has been purified. Furthermore, intraflagellar transport and rafts can be studied in two excellent genetic systems, one (C. elegans) with a completely sequenced genome. Little is known about the physical relationship between microtubule motors and their cargoes in any transport processes, and answers to questions about intraflagellar transport should help fill that gap. How do motor proteins bind to rafts? And what is the relationship between rafts and axoneme subunits? Perhaps components such as tubulin and flagellar dynein associate directly with the A and B complexes and are carried as resolute cargoes [13]. At the other extreme, there might be no direct association: rafts might act as simple impellers, displacing cytosol along the narrow space between the outer doublets and plasma membrane, thereby facilitating the diffusion of axoneme subunits. Whatever the truth turns out to be, real answers to questions about both motor–cargo relationships and the movement of materials along axonemes are on the horizon. Acknowledgements Support was provided by an Established Investigatorship from the American Heart Association with funds provided in part by the AHA Indiana Affiliate Inc.
References 1. Dutcher SK: Flagellar assembly in two hundred and fifty easy-to-follow steps. Trends Genet 1995, 11:398-404. 2. Johnson KA, Rosenbaum JL: Polarity of flagellar assembly in Chlamydomonas. J Cell Biol 1992, 119:1605-1611. 3. Rosenbaum JL, Moulder JE, Ringo DL: Flagellar elongation and shortening in Chlamydomonas. The use of cycloheximide and colchicine to study the synthesis and assembly of flagellar proteins. J Cell Biol 1969, 41:600-619. 4. Rosenbaum JL, Cole DG, Diener DR: Intraflagellar transport: the eyes have it. J Cell Biol 1999, 144:385-388. 5. Kozminski KG, Johnson KA, Forscher P, Rosenbaum JL: A motility in the eukaryotic flagellum unrelated to flagellar beating. Proc Natl Acad Sci USA 1993, 90:5519-5523.
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6. Cole DG, Diener DR, Himelblau AL, Beech PL, Fuster JC, Rosenbaum JL: Chlamydomonas kinesin-II-dependent intraflagellar transport (IFT): IFT particles contain proteins required for ciliary assembly in Caenorhabditis elegans sensory neurons. J Cell Biol 1998, 141:993-1008. 7. Pazour GJ, Wilkerson CG, Witman GB: A dynein light chain is essential for the retrograde particle movement of intraflagellar transport (IFT). J Cell Biol 1998, 141:979-992. 8. Kozminski KG, Beech PL, Rosenbaum JL: The Chlamydomonas kinesin-like protein FLA10 is involved in motility associated with the flagellar membrane. J Cell Biol 1995, 131:1517-1527. 9. Lux III FG, Dutcher SK: Genetic interactions at the FLA10 locus: suppressors and synthetic phenotypes that affect the cell cycle and flagellar function in Chlamydomonas reinhardtii. Genetics 1991, 128:549-561. 10. Walther Z, Vashishtha M, Hall JL: The Chlamydomonas FLA10 gene encodes a novel kinesin-homologous protein. J Cell Biol 1994, 126:175-188. 11. Pazour GJ, Dickert BL, Witman GB: The DHC1b (DHC2) isoform of cytoplasmic dynein is required for flagellar assembly. J Cell Biol 1999, 144:473-481. 12. Porter ME, Bower R, Knott JA, Byrd P, Dentler WL: Cytoplasmic dynein heavy chain 1b is required for flagellar assembly in Chlamydomonas. Mol Biol Cell 1999, 10:693-712. 13. Piperno G, Mead K: Transport of a novel complex in the cytoplasmic matrix of Chlamydomonas flagella. Proc Natl Acad Sci USA 1997, 94:4457-4462. 14. Collet J, Spike CA, Lundquist EA, Shaw JE, Herman RK: Analysis of osm-6, a gene that affects sensory cilium structure and sensory neuron function in Caenorhabditis elegans. Genetics 1998, 148:187-200. 15. Lewis JA, Hodgkin JA: Specific neuroanatomical changes in chemosensory mutants of the nematode Caenorhabditis elegans. J Comp Neurol 1977, 172:489-510. 16. Morris RL, Scholey JM: Heterotrimeric kinesin-II is required for the assembly of motile 9+2 ciliary axonemes on sea urchin embryos. J Cell Biol 1997, 138:1009-1022. 17. Nonaka S, Tanaka Y, Okada Y, Takeda S, Harada A, Kanai Y, Kido N, Hirokawa N: Randomization of left-right asymmetry due to loss of nodal cilia generating leftward flow of extraembryonic fluid in mice lacking KIF3B motor protein. Cell 1998, 95:829-837. 18. Beech PL, Pagh-Roehl K, Noda Y, Hirokawa N, Burnside B, Rosenbaum JL: Localization of kinesin superfamily proteins to the connecting cilium of fish photoreceptors. J Cell Sci 1996, 109:889-897. 19. Marszalek JR, Liu X, Roberts E, Chui D, Marth J, Williams DS, Goldstein LB: Tissue specific deletion of KIF3A from photoreceptors results in their degeneration. Mol Biol Cell 1998, 9:131a. 20. Wick MJ, Ann DK, Loh HH: Molecular cloning of a novel protein regulated by opioid treatment of NG108-15 cells. Brain Res Mol Brain Res 1995, 32:171-175.