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Share Flipboard Email. Regina Bailey. Biology Expert. Regina Bailey is a board-certified registered nurse, science writer and educator. What Are Cilia and Flagella? Featured Video. Cite this Article Format. The conference was initiated with a report by Douglas Cole University of Idaho on how the polypeptides of Complex B are associated with one another.
Work on purified Complex B has indicated there is a core particle comprised of three polypeptides IFT46, 52, and 88 on which the remaining Complex B polypeptides assemble. Reports by both Daniela Nicastro Brandeis University on the structure of ciliary axonemes and dynein, and Takashi Ishikawa ETH, Zurich on the dynein complex of wild-type and mutant Chlamydomonas , provided new three-dimensional information on the dynein motor complex and how it may be functioning to cause microtubule outer doublet sliding.
However, these two groups differed in their reports with respect to the angle of orientation the outer arm dynein heads have relative to the doublet microtubules, which has important implications for the mechanism of force generation by the multi-headed dynein. Both reports were founded on the elegant negative stain images of the dynein motor by Stan Burgess University of Leeds who presented single-particle analysis of the circular motor head of the dynein heavy chain and how it might be moving.
Using replicas obtained by quick freeze-deep etching, Pietro Lupetti University of Siena reported that the two dynein heads are positioned at different distances from the A-tubule. Furthermore, the stalk and the stem domains do not reside in the same plane as the head, which is contrary to what had been previously reported for isolated dynein adsorbed to a flat surface.
In the first use of tomography to study the structure of IFT particles, Gaia Pigino University of Siena showed that these are complex structures, but that periodicities of 8. Reports on dynein structure were complemented by biochemical analyses of the dynein motor complex by Stephen King University of Connecticut Health Center and continued in reports on the control of dynein activity by the dynein regulatory complex DRC by Mary Porter University of Minnesota , the role of calmodulin and the radial spokes in the control of flagellar beating by Elizabeth Smith Dartmouth College , and the function of kinases and phosphatases, some associated with the flagellar radial spokes, in the control of dynein activity by Winfield Sale Emory University and by Avanti Gokhale Emory University.
Additional important analyses of the diverse, functional capabilities of dynein subforms and domains were described by Ritsu Kamiya University of Tokyo , and new advances on dynein regulation were presented by Chikako Shingyoji University of Tokyo. Part of the dynein control mechanism involves the orientation of the central pair microtubules, and David Mitchell SUNY Upstate Medical University provided an update on how this complex central pair apparatus rotates, modulating the radial-spoke based activity of the dynein arms in different halves of the doublet circle.
This central pair complex also contains kinesin Bernstein et al. One of the highlights of the meeting was a group of talks on the control of ciliary length and stability, and ciliary resorption, in particular as a prelude to cell division. Although IFT is involved in length control because it delivers the required axonemal and membrane precursors to the flagellum Qin et al. Paul Lefebvre University of Minnesota has defined this system in an elegant fashion using the long-flagella lf mutants of Chlamydomonas that grow flagella to two or three times their normal length.
In addition, William Dentler University of Kansas reported that disruption by Brefeldin A of membrane delivery to the flagellum from the Golgi induced flagellar disassembly and inhibited flagellar assembly without affecting IFT.
A related series of presentations addressed the relationship between resorption of the primary cilium and the ability of the cell to exit G o and reenter the cell cycle. This cilia—cell cycle control hypothesis has been discussed for decades, but other than an observed correlation between cilia resorption and cell cycle progression no direct cause-and-effect data have been presented. This has been remedied by several sets of data addressing cell cycle control. First, Lynne Quarmby Simon Fraser University showed how mutations in the Cnk and Nek kinases of which there are many different ones in ciliated organisms of Chlamydomonas affected flagellar resorption and the cell cycle.
Second, Erica Golemis Fox Chase Cancer Center reported an interaction between the cell cycle kinase Aurora A and the pro-metastatic scaffolding protein HEF1 that occurs at the basal body in response to external cues. This interaction activates Aurora A kinase activity, the target of which is HDAC6, a deacetylase that removes the acetate group from axonemal tubulin, thus destabilizing the axoneme as a prelude to disassembly of the primary cilium.
Tubulin deacetylation by HDAC6 is necessary and sufficient for cilia destabilization and resorption, and this is required for entry into the cell cycle from Go Pugacheva et al. Interestingly, Pan et al. Third, the coregulation of the cilia cycle and the cell cycle was nicely documented by Zhaohui Wang Yale University , who presented evidence that IFT27, a small G protein and a component of IFT Complex B, also plays a role in cell division.
When the concentration of IFT27 decreases below a certain level, resorption of the flagella is induced, and the cell enters S-phase.
A rise in IFT27, due to new transcription, is then required for the completion of cell division. If IFT27 does not rise i. IFT particles moving via the activity of kinesin-2 in the anterograde direction toward the tip of the flagellum carry inactive cytoplasmic dynein as cargo; the particles turn around at the tip and head back to the cytoplasm after releasing their cargo and picking up turnover products at the tip.
During this process, activation of cytoplasmic dynein 2 and inactivation of kinesin-2 occur. This complex series of activities takes place with hardly a pause, and Lotte Pedersen University of Copenhagen presented an analysis of EB1 microtubule end binding protein 1 , which localizes to the flagellar tip Pedersen et al.
Pedersen also reported that EB1 is required for primary cilia formation in fibroblasts. In another approach to flagellar tip analysis, Roger Sloboda Dartmouth College reported data derived from analysis of flagella by difference gel electrophoresis, showing that flagella contain elements of a protein methylation pathway. Three specific but as-yet-unidentified proteins of the axoneme contain methyl-arginine residues.
Analysis of the events occurring at the tip is further complicated by the presence there of kinesin, a motor protein known to mediate tubulin dimer removal from the plus ends of microtubules. Scott Dawson University of California, Davis showed that a kinesin mutation SN caused elongation of flagella in Giardia, and this has also been recently demonstrated in Leishmania by Blaineau et al. It was already known from work on targeting glucose receptors to the trypanosome membrane that specific sequences are required for entry into the flagellar compartment Piper et al.
New work presented by Dusanka Deretic University of New Mexico showed that a sequence motif VxPx in rhodopsin is required for the interaction of rhodopsin with accessory transport proteins and entry of rhodopsin into the connecting cilium and rod outer segment Fig. Rather, the protein accumulates around the base of the cilium. Gregory Pazour University of Massachusetts Medical School reported a C-terminal, residue motif that targets fibrocystin to the cilium.
Pazour had shown earlier that IFT20 could be found at the Golgi, and was, at least in part, responsible for shepherding vesicles which would become part of the ciliary membrane to their point of exocytosis adjacent to the basal body.
It is thought that at this point IFT moves membrane-associated cargo to the ciliary membrane. Hence, it is here that the targeting sequences on ciliary membrane proteins are presumably recognized, i. Uwe Wolfrum Johannes Gutenberg University of Mainz described a protein network related to human Usher syndrome combined blindness and deafness that defines a specialized membrane domain in the apical, pericilliary region of the inner segment that serves as a target for vesicles destined for movement through the connecting cilium to the outer segment of photoreceptor cells.
Christine Insinna Medical College of Wisconsin demonstrated a requirement for Kif17 the mammalian homologue of worm Osm-3 for rod outer segment development but not for kidney cilia development , perhaps to move along singlet microtubules as occurs in Caenorhabditis elegans Snow et al. Philipp Trojan Johannes Gutenberg University of Mainz reported that the light dependent phosphorylation of centrin regulates the movement of transducin through the connecting cilium and into the outer segment.
Maureen Barr Rutgers University , working on the nephrocystins in the worm, proposed that these proteins function at the transition zone to dock and organize IFT particles, thus regulating access to the cilium. An exciting new development in ciliary assembly and function in relation to disease Table I concerns the Bardet-Biedl syndrome BBS proteins. BBS is a disease syndrome resulting in a large array of pathologies, including obesity, defective bone development, diabetes, and other developmental disorders; there are at least 12 different BBS genes and the BBS proteins are located primarily in the centrosome—ciliary complex Nachury et al.
Max Nachury from the Peter Jackson group, Genentech and Stanford reported that many of the BBS proteins sediment together on gradients as a complex, called the BBSome, providing some of the first evidence that the diverse pathologies resulting from mutations in the different BBS genes are related.
Unfortunately, primary cilia cannot yet be isolated in sufficient quantities from tissue culture cells, or from C. The Genentech group, collaborating with Val Sheffield University of Iowa , hypothesized that the BBSome is involved in the movement of ciliary membrane vesicles from the cytoplasm to the cilia surface.
Related data from Gregory Pazour University of Massachusetts Medical School showed that RAb8 is important for opsin transport to the OS; a mutation in Rab8 causes opsin to remain in the inner segment in photoreceptor cells.
Systemic loss of cilia in adult mice results in animals that eat too much hyperphagia and are thus obese and have related defects, such as problems with glucose homeostasis. It is now relatively clear that the primary cilia of cells in developing tissues such as mammary gland and bone are absolutely essential for normal tissue morphogenesis. Tubule branching in the mammary gland is greatly inhibited, and bone development likewise is highly abnormal, including polydactyly and improper bone length.
The exact role of the primary cilia in the morphogenesis of these tissues is not yet known, but it almost certainly is going to involve a role in cell polarity during embryogenesis and subsequent postnatal development.
This resulted in a loss of the primary cilium the kinocilium , and a defect in the organization of the stereocilia which are actin-based microvilli. Using genetics combined with image analysis, Wallace Marshall University of California, San Francisco has begun to identify the basal body components required for positioning, while Susan Dutcher Washington University reviewed the basal body mutants in Chlamydomonas that assemble morphologically abnormal basal bodies.
These mutants all have consistent phenotypes: flagellar assembly defects, errors in cleavage furrow placement, and supersensitivity to taxol. In interesting work on the role of primary cilia in wound healing reported by Christensen University of Copenhagen , it is clear that the cells which are moving to close the wound all have their primary cilia pointing in the direction of cell movement, whereas the nonmotile cells behind the wound do not.
There are now many reported examples of how primary cilia sense the environment either by mechano-, chemo-, or photoreceptors on the membrane of the primary cilium. William Snell University of Texas Southwest Medical Center reported a role for several different kinases in the mating reaction in Chlamydomonas ; this event depends on interaction of the flagella of plus and minus mating types and requires a functional IFT system.
Two years ago Haycraft et al. Perhaps the most detailed work on receptors associated with cilia has been performed on polycystins 1 and 2 PC1 and 2, the gene products of PKD1 and 2, respectively , which are found on the ciliary membrane, in addition to other areas in the cell such as the ER and the apical cell surface. The resultant calcium flow into the cell keeps the cell in the nondividing state.
Michael Caplan Yale University showed that the C terminus then finds its way into the nucleus, activating signaling pathways that modulate the uncontrolled cell division characteristic of PKD.
This hypothesis of PKD pathogenesis via regulated intramembrane proteolysis Brown et al. Loss of PC1 at any point before this time resulted in severely cystic kidneys within three weeks, while loss of PC1 after this critical two-day period did not result in a cystic pathology for as long as five months.
So, although cilia are indeed important in normal kidney development and maintenance Pazour et al. For example, Stefan Somlo Yale University also presented data on the flow hypothesis of PKD, suggesting that calcium flux could occur in the kidney tubule cells when PC2 is not present in the cilia, by use of a mutant form of PC2 that retains its ability to act as a calcium channel but that does not localize to the primary cilium. Thus, PC2 is required for the calcium response, but it appears that ciliary PC2 is not required.
However, the most direct positive evidence for the mechanosensory activity of kidney cilia continues to be the work of Praetorius and Spring , who showed that moving a single cilium caused calcium entry into that cell. Continuing this work using freshly isolated renal tubules, Helle Praetorius University of Aarhus reported that renal flow induces activation of purinergic P2 receptors, resulting in a calcium increase that could be inhibited by externally applied ATP scavengers such as apyrase.
Thus, flow may be inducing an ATP release that in turn activates purinergic P2 receptors leading to the calcium increase. Note that the matter is far from settled, however, because one class of P2 receptors P2YR has the ability to release calcium from internal stores Song et al.
The activity of receptors and calcium in the cilium requires now a return to the discussion of situs inversus introduced at the beginning of this review. Nobutaka Hirokawa University of Tokyo proposed that the flow moves vesicles filled with morphogens sonic hedgehog and retinoic acid from right to left Tanaka et al. Alternatively, Martina Brueckner Yale University proposed that the two populations of cilia present in the node recall Caspary et al.
Those in the center of the node are motile and are responsible for the leftward fluid flow, which in turn bends the nonmotile cilia on the left side of the node, inducing calcium flow through ciliary PKD channels McGrath et al.
Asymmetry of inversin localization in cells on the left side of the node also occurs, and this is thought to lead to activation of signaling pathways that ultimately results in asymmetric morphogenesis of the body organs.
A very important series of results were reported linking cilia abnormalities to a range of human diseases beyond those PKD, BBS already mentioned.
Karl Lechtreck University of Massachusetts Medical School showed that the protein hydin—first identified as a component of one of the central pair structures in Chlamydomonas that were so elegantly detailed by David Mitchell SUNY Upstate Medical University —is involved in the development of hydrocephalus cerebrospinal fluid accumulation in brain ventricles. In stunningly beautiful videos of ciliary motility on cells lining the brain ventricles, hydin-deficient ependymal cilia were observed to be stiff and unable to form the beat pattern characteristic of normal cilia.
Hydrocephalus develops presumably because a lack of proper motility results in decreased fluid transport. In a related presentation, Heymut Omran University Children's Hospital, Freiburg reported for the first time that a mutation in the DNAI2 gene encoding outer arm dynein intermediate chain 2 results in primary ciliary dyskinesia characterized by defects in motile cilia of the respiratory tract, embryonic node, and sperm in some patients.
Meckel-Gruber syndrome is a rare recessive disorder characterized by cystic kidneys, polydactyly, and incomplete skull closure.
Helen Dawe University of Oxford showed that Meckel-Gruber syndrome proteins Mks1 localized to the centrosome and MKS3 meckelin, localized to the primary cilium are required for centrosome migration and subsequent ciliogenesis, perhaps through interactions with Rho kinase and myosin II. Thus, in the absence of cilia due to the loss of a key basal body component, malformations of the face, oral cavity, and digits, which together with PKD are characteristics of OFD syndrome, occur.
Surprisingly, loss of OFD1 does not affect the cell cycle in embryonic stem cells in culture. Anatoliy Masyuk Mayo Clinic showed that the basal bodies in this rat model are heterogeneous in size, contain extra appendages, and are positioned incorrectly in the cell. These structural and functional abnormalities cause hepatic cystogenesis. Cystin has an N-terminal myristoylation signal, a ciliary localization signal, and two nuclear localization signals.
Often, but not always, cystin resides at the ciliary tip. Lisa Guay-Woodford University of Alabama showed that a myristoyl-electrostatic switch McLaughlin and Aderem, controls the cycling of cystin on and off the membrane and hence the localization of cystin to the cilium or the nucleus.
The S17A mutation enhances the association of cystin with the ciliary membrane, preventing its nuclear localization; when in the nucleus, however, cystin interacts with necdin and affects the expression of renal cell genes. Among these are cdc2 and c-myc, the former explaining why inhibitors of cyclin-dependent kinases are effective in treating cystic disease in the mouse kidney.
In addition, flr mutant cilia are short, and lack the outer side of the B-tubule of the axoneme, which is where polyglutamylated tubulin is located Redeker et al.
Thus, flr protein is involved, perhaps as a cofactor, in tubulin glutamylation. The C. Finally, Uwe Wolfrum Johannes Gutenberg University of Mainz presented clear electron microscopic evidence showing that IFT proteins can be found on vesicles near the synapse in rod inner segments before vesicle docking and fusion with the periciliary membrane.
These data are consistent with the hypothesis of Jekely and Arendt , who have proposed that the cilium originally derived from a specialized membrane patch to which coated vesicles were transported by primordial IFT machinery. Furthermore, the work of Wolfrum points out the importance of this transport network for cilia assembly and should caution investigators interpreting, for example, knock-down experiments with cilia or IFT-related proteins.
A knock-down phenotype may not have anything to do directly with the ciliary apparatus itself, but perhaps to some component of the steps of vesicle budding, transport, and fusion that are required in the cytoplasm before the actual formation of a cilium or flagellum. So many significant and outstanding advances were reported at this meeting that it is impossible to single out one or two key results to highlight here. Those readers interested in obtaining further information on the topics discussed at the meeting should consult some recent reviews Rosenbaum and Witman ; Sloboda ; Scholey and Anderson ; Singla and Reiter ; Pan and Snell ; Yoder
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