Intraflagellar transport

REVIEWS

Cilia and flagella (BOX 1) contain a long microtubularaxoneme surrounded by an external membrane thatis continuous with the plasma membrane of the cell.At its proximal end, the axoneme is continuous with abasal body, which anchors it in the cell. During ciliaryor flagellar growth, the axoneme is assembled by theaddition of new axenomal subunits to its distal tip1–5.Because cilia and flagella lack the machinery that isnecessary for protein synthesis, the site of assembly ofthe axoneme is far removed from the site of synthesisof axonemal proteins in the cell body. This posesproblems for the delivery of new axonemal buildingblocks to their site of assembly.

The cell has solved this logistical problem by meansof intraflagellar transport (IFT). During IFT, non-membrane-bound particles are moved continuouslyalong the axonemal doublet microtubules, just beneaththe flagellar membrane, from the base to the tip of theorganelle. IFT particles moving in this anterogradedirection are thought to carry materials for the assem-bly and maintenance of the flagellar axoneme andmembrane. At the tip of the flagellum, the IFT particlesreverse direction and are then transported back to thebase of the flagellum, where they are returned to a largepool of IFT components in the region surrounding thebasal body. Movement in this retrograde direction recy-cles the IFT particles and motors. This IFT process isessential for the formation of cilia and flagella — defectsin IFT lead to defects in the assembly of motile flagellain Chlamydomonas reinhardtii 6–8, sea urchin9 andTetrahymena thermophila10, of ciliated sensory neuronsin Caenorhabditis elegans11–16, and of NODAL CILIA17–20, kid-ney primary cilia8 and rod outer segments in mice21,22.

In this article, we review briefly the discovery ofIFT, the nature of the IFT motors and particles, andthe results of disrupting IFT in model organisms. Ofparticular interest, recent phenotypic analyses of micewith defects in IFT motors and particle proteins haveshown a previously unsuspected involvement of IFTand cilia in polycystic kidney disease, SITUS INVERSUS

and retinal degeneration. Finally, we discuss new find-ings and hypotheses on the roles of IFT in the sortingand targeting of proteins to the flagellar compart-ment, in controlling flagellar length, and in signaltransduction between the flagella and the cell body.Aspects of IFT have also been reviewed in a reportthat is based, in part, on a recent meeting23.

First sightings of intraflagellar transportMuch of our knowledge of the protein machinery andthe basic biology of IFT has come from studies of thebiflagellate alga Chlamydomonas reinhardtii, which isan excellent model system for the biochemical andmolecular-genetic analyses of proteins and processesthat occur in the flagellum. IFT was first observed inChlamydomonas using differential interference con-trast (DIC) microscopy24, where particles were seen tomove anterogradely along the flagellum at ~2.5 µm s-1

without pausing, whereas apparently smaller particleswere seen to move retrogradely at ~4 µm s-1 (forQuick-Time video, see Online link to Rosenbaum LabResearch Summary). Correlative light microscopyand electron microscopy (EM) showed that the mov-ing particles were organized in linear arrays6 (FIG. 1).Electron micrographs of the arrays showed that theywere connected by periodic links to both the flagellar

INTRAFLAGELLAR TRANSPORTJoel L. Rosenbaum* and George B. Witman‡

Eukaryotic cilia and flagella, including primary cilia and sensory cilia, are highly conservedorganelles that project from the surfaces of many cells. The assembly and maintenance of thesenearly ubiquitous structures are dependent on a transport system — known as ‘intraflagellartransport’ (IFT) — which moves non-membrane-bound particles from the cell body out to the tipof the cilium or flagellum, and then returns them to the cell body. Recent results indicate thatdefects in IFT might be a primary cause of some human diseases.

NATURE REVIEWS | MOLECULAR CELL BIOLOGY VOLUME 3 | NOVEMBER 2002 | 813

*Department of Molecular,Cellular and DevelopmentalBiology, Yale University, NewHaven, Connecticut 06520,USA and ‡Department ofCell Biology, University ofMassachusetts MedicalSchool, Worcester,Massachusetts 01655, USA.Correspondence to G.B.W.e-mail: [email protected]:10.1038/nrm952

NODAL CILIA

(Also called monocilia). Theprimary cilia that are located onthe ventral surface of the nodeof the early mammalianembryo. They are unusualamong primary cilia in that theyare motile. This motilitygenerates a directional fluid flowacross the node, which initiatessignalling events that lead to thenormal development ofleft–right asymmetry in theorganism.

SITUS INVERSUS

A condition in which internalbody organs are in an inverseposition relative to normal.

© 2002 Nature Publishing Group

PLUS OR MINUS END

Microtubules are polarstructures that grow morerapidly by the addition of newsubunits to one end (the ‘plus’end) than to the other end (the‘minus’ end). The minus ends offlagellar outer doubletmicrotubules are continuouswith the microtubules of thebasal body, and their plus endsare at the distal tip of theflagellum.

814 | NOVEMBER 2002 | VOLUME 3 www.nature.com/reviews/molcellbio

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are orientated with their plus ends at the distal tip ofthe organelle2,27. Therefore, there must be separatemotors for anterograde and retrograde IFT.Microtubule motors fall into two large superfamilies— kinesins and dyneins28. The specific motors thatmove the IFT particles (FIG. 2) were defined usingChlamydomonas flagellar mutants that were defectivefor the genes encoding motor subunits.

The anterograde motor. Studies of flagellar assembly(fla) mutants29,30 in Chlamydomonas first identified

membrane and the B-tubule of the outer doubletmicrotubule6,24,25. More recently, IFT has been visual-ized in both the ciliated sensory neurons of C. ele-gans 14,16,26 and the primary cilia of mouse kidney cells(G. J. Pazour, unpublished data) using green fluores-cent protein (GFP)-tagged IFT proteins.

Motors that power intraflagellar transportAll microtubule-based motors move along micro-tubules in a single direction, towards either the PLUS OR

MINUS END of the microtubule. All flagellar microtubules

Box 1 | Cilia and flagella

Cilia and flagella are longappendages that extend fromthe cell body (see panel a).When these structures occurtogether in large numbersthey are usually referred to as‘cilia’ , as in mammaliantracheal cilia (see panel b),and when they occur singly orin small numbers they arereferred to as ‘flagella’, as in themammalian sperm flagellum.In either case, they havealmost the same internalstructure, are composed ofmany of the same proteinsand have the sameintraflagellar transportsystem. Therefore, the termscilia and flagella are usedinterchangeably in this review.

In nearly all motile cilia, theinternal structure consists of a‘9+2’ axoneme that containsnine outer doubletmicrotubules and two centralmicrotubules (see panels cand d). The axoneme alsocontains inner and outerdynein arms, which generatethe force for motility, andradial spokes and central pairprojections, which regulatethe motile machinery.At itsbase, the axoneme is continuous with the basal body, which consists of a ring of three triplet microtubules. Theorganization and functioning of these structures are reviewed in detail in REF. 99.

Many vertebrate cells contain a single cilium called a ‘primary’ cilium100 (see Online link to the Primary Cilium ResourcePage). In general, primary cilia are non-motile and have a ‘9+0’ axoneme that lacks the central pair of microtubules presentin motile cilia. However, at least some primary cilia — those on embryonic nodal cells — are motile. The functions ofprimary cilia are not clear, but they are likely to be sensory. In some cases, primary cilia have been highly modified for aspecialized sensory function, such as photoreception in vertebrates (see FIG. 6 legend), and chemoreception andmechanoreception in nematodes and insects.

The figure shows scanning electron micrographs (SEMs) of flagella extending from a Chlamydomonas cell (a) and of ciliaon mouse tracheal cells (b). The structure of the flagellar axoneme is seen in an electron micrograph (c) and a diagram (d)of a cross-section of a Chlamydomonas flagellum.A and B,A- and B-tubules of outer doublet microtubules; CPP,projections from the central pair of microtubules; FM, flagellar membrane; IA, inner dynein arms; OA, outer dynein arms;RS, radial spokes. Image b was kindly provided by Yvonne Vucica, University of Massachusetts Medical School, USA. Partsc and d were modified with permission from REF. 99. © (2002) Plenum, New York, USA.

c d

a b

RS CPP

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FM

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the 85-kDa subunit, in the flagella by using gold-labelled antibodies and EM showed that it was locatedbetween the flagellar membrane and outer doubletmicrotubules, where IFT takes place6. Surprisingly,however, immunofluorescence microscopy indicatedthat most of the Fla10 was located at the base of theflagella, around the basal bodies7,12,35,36 (see below).

The retrograde motor. Cytoplasmic dynein was firstimplicated in IFT when it was found that a mutationin the gene encoding Chlamydomonas LC8 — a cyto-plasmic dynein light chain — resulted in cells withshort flagella that grew initially to only ~50–75 % oftheir normal length, and then shortened gradually25.These flagella had normal levels of anterograde IFT,but had greatly reduced levels of retrograde IFT. As aresult, the mutant Chlamydomonas accumulated largenumbers of IFT particles at the tips of their short fla-gella, and western blots showed that the isolated fla-gella contained 10–20 times the normal amounts ofIFT-particle polypeptides25 (see below). These resultsindicated that the retrograde motor for IFT might bedefective in the mutant. However, LC8 is also a com-ponent of other protein complexes, including outerarm dynein, inner arm dynein and myosin V (REFS

37,38), so it was not clear which motor was responsiblefor the loss of retrograde IFT.

More definitive results were obtained by deletingthe gene that encodes the Chlamydomonas dyneinheavy chain isoform DHC1b. Previous studies hadshown that the predicted amino-acid sequence ofDHC1b (known as Dhc2 in mammals) is most closelyrelated to that of the conventional cytoplasmic dyneinheavy chain DHC1a39,40 (known as Dhc1 in mam-mals), but that in sea urchins its expression is upregu-lated by de-ciliation, as is the case for axonemaldyneins39. This indicated that DHC1b representseither a true axonemal dynein, the amino-acidsequence of which resembles that of cytoplasmicdynein, or a cytoplasmic dynein that is involved in cil-iary regeneration39.

This, together with the results of theChlamydomonas LC8-mutant study, made DHC1b astrong candidate for a retrograde IFT motor subunit.When the DHC1b gene was deleted fromChlamydomonas, the resulting mutants grew anddivided normally, but had very short flagella that accu-mulated even more IFT particles than did the LC8mutant7,41. These results indicated that DHC1b is infact a subunit of a specialized cytoplasmic dynein thatfunctions as the retrograde motor for IFT. Apparently,IFT particles were moved into the mutant flagellum bythe action of kinesin-II, but they could not be returnedto the base of the flagellum owing to the absence of theretrograde motor. Western blotting and immunofluo-rescence microscopy confirmed that DHC1b was pre-sent in the wild-type flagellum and had the same dis-tribution as the IFT particles7 (see below).

When a temperature-sensitive mutant of DHC1bwas allowed to form flagella at the permissive temper-ature and then shifted to restrictive temperature, the

the gene FLA10 (REF. 31), which is now known toencode a kinesin-II motor subunit that is present inthe flagellum. Cells with temperature-sensitive (ts)alleles of FLA10 are unable to form flagella at therestrictive temperature32. Shifting fla10ts mutant cellswith fully formed flagella to the restrictive tempera-ture resulted in loss of the flagella by gradual shorten-ing6,29. This shortening was correlated with the cessa-tion of IFT and the disappearance of the IFT particlesfrom the flagella6. Moreover, if fla10ts cells that hadformed flagella at the permissive temperature werethen shifted to the restrictive temperature and defla-gellated, they could not regenerate their flagella6,29.Therefore, it seemed that IFT and Fla10 were essentialfor both the assembly and the maintenance of the fla-gella. As Fla10 was shown to be a kinesin32 with thestructural properties of a microtubule-plus-end-directed motor33, it was proposed that anterogradeIFT was powered by Fla10 (REF. 6).

Fla10 was subsequently recognized to be a memberof the kinesin-II family of heterotrimeric, micro-tubule-plus-end-directed kinesins34. Furthermore, itwas shown that, in sea urchin blastulae9, the injectionof antibodies that had been raised against a motorsubunit of kinesin-II led to the formation of short,paralysed cilia that lacked the central pair of micro-tubules, and that, in mouse embryos, the nodal ciliadid not assemble when either of the motor subunitgenes of kinesin-II were knocked out17–19. Therefore,kinesin-II is probably the anterograde IFT motor inall cilia and flagella.

The flagellar Fla10 kinesin-II was purified tohomogeneity12 and shown to be a typical het-erotrimeric kinesin-II that is composed of two motorsubunits of 85 and 95 kDa, known as KIF3A andKIF3B in mammals (REF. 34), and a non-motor subunitof 115 kDa, known as kinesin-associated protein34

(KAP). Regardless of the method used for its purifica-tion, the Fla10 kinesin-II was not associated withother flagellar polypeptides12. Localization of Fla10,

Figure 1 | The structure of intraflagellar transport particles. Electron micrograph of alongitudinal section through a Chlamydomonas flagellum showing linear arrays of intraflagellartransport (IFT) particles (arrowheads) between the outer doublet microtubules and the flagellarmembrane. Note the links between the rows of IFT particles and the outer doublet microtubules,as well as the close association between the IFT particles and the flagellar membrane.Reproduced with permission from REF. 6 © (2002) Rockefeller University Press.

100 nm

Outer doubletmicrotubule

Flagellar membrane

Outer doubletmicrotubule

Flagellar membrane

IFT particles

IFT particles



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The Chlamydomonas DHC1b deletion mutant alsoshowed that IFT particles are recycled after they arereturned from the flagellum to the cell body. In wild-type Chlamydomonas, most of the IFT particles arelocalized around the basal bodies7,12 (see below). But,in the dynein 1b retrograde mutant, the particles arecompletely redistributed from the peri-basal-bodyregion to the flagella, presumably because they aretrapped in the flagella and cannot be returned to theirsites around the basal bodies7. Further evidence thatIFT proteins are recycled came from experiments inwhich IFT in Chlamydomonas flagella was observed tocontinue unabated despite a nearly complete inhibi-tion of protein synthesis by treatment with ani-somycin43.

Control of intraflagellar transport. Kinesin-II is car-ried as IFT cargo from the flagellar tip to the base7,14,25.Conversely, because dyneins are motors that activelymove towards the microtubule-minus-end, it can beinferred that cytoplasmic dynein 1b is carried as IFTcargo to the tip. There is evidence that at least someflagellar precursors — for example, the inner dyneinarms — are also transported by IFT particles to thesite of axonemal assembly at the flagellar tip and arereleased there5. At the tip, the apparent size of the par-ticles is reduced24,44 (possibly due, in part, to unload-ing of axonemal precursors), the kinesin motorbecomes cargo and the cytoplasmic dynein 1b motortakes over to transport the particles back to the peri-basal-body region. Moreover, although IFT particlesmove anterogradely more slowly than they move ret-rogradely6,24,25,44, retrograde particles are more numer-ous, which indicates that particle remodelling alsomust occur at each end of the flagellum43.

The mechanisms by which IFT-particle turn-around, cargo loading and release, and motorexchange occur at the base and tip of the flagellum areunknown, but, by analogy with other bidirectionalparticle-movement systems (for example, MELANOPHORE

movement45), it might involve phosphorylation anddephosphorylation of motors and/or their associatedproteins. Because the IFT particles move unidirection-ally without stopping or reversing, the regulatory pro-teins that turn kinesin on and dynein off must behighly localized at the base of the flagellum; con-versely, the proteins that turn kinesin off and dyneinon must be highly localized at the tip of the flagellum.At the base of the flagellum, the regulatory proteinsmight be anchored to the TRANSITION FIBRES (see below).The tip of the flagellum also contains specializedstructures that might function as anchors for the pro-teins that turn kinesin off and dynein on. For exam-ple, each of the A-tubules of the outer doublet micro-tubules is terminated by a plug that is connected to theflagellar membrane by a thin filament46,47.

IFT particles and particle proteinsWhen Chlamydomonas fla10ts-mutant cells are shiftedto the restrictive temperature, the number of IFT parti-cles in the flagella decreases by ~70% before the flagella

flagella shortened42. Therefore, retrograde IFT is nec-essary for the maintenance of fully formed flagella,although its role might be simply to recycle the com-ponents that are necessary for anterograde IFT.

In C. elegans, the homologue of DHC1b is CHE-3(REFS 14,15), and mutations in che-3 result in a pheno-type very similar to that seen in DHC1b mutants inChlamydomonas: the sensory cilia are very short andfilled with IFT particles13,15. Moreover, che-3 mutantslack retrograde IFT14. So, cytoplasmic dynein 1b(which contains DHC1b), or its homologues of vari-ous names in other organisms, is likely to be the retro-grade IFT motor in all cilia and flagella.

Figure 2 | The intraflagellar transport machinery. During intraflagellar transport (IFT), lineararrays of IFT particles (yellow) are transported towards the ‘plus’ (distal) ends of the flagellar outerdoublet microtubules (blue) by kinesin-II (pink), and towards the ‘minus’ (proximal) ends of themicrotubules by cytoplasmic dynein 1b (green). The IFT particles, which are composed of at least16 different proteins, are believed to be carrying precursors that are necessary for the assembly ofthe flagellar axoneme. The IFT particles are linked to the flagellar membrane (grey lines), whichindicates that their cargo might also include membrane proteins.

Flagellar membrane

B-tubules of outerdoublet microtubules

IFT particles

Kinesin-II

Cytoplasmic dynein 1b

(–) (+)

Table 1 | Intraflagellar-transport-particle polypepetides

Complex type Chlamydomonas Caenorhabditis elegans

Complex A* IFT144 -IFT140 CHE-11IFT139 -IFT122 DAF-10

Complex B IFT172 OSM-1IFT88 OSM-5IFT81 -IFT80 -IFT74/72‡ -IFT57/55‡ CHE-13IFT52 OSM-6IFT46 -IFT27 -IFT20 -- CHE-2§

The table shows the intraflagellar-transport (IFT)-particle polypeptides in Chlamydomonas, and theirCaenorhabditis elegans homologues. The C. elegans genes encoding the IFT-particle proteins wereoriginally identified by selecting mutants defective in behaviours dependent on sensory cilia, includingchemotaxis (CHE), dauer larva formation (DAF), and avoidance of solutions of high osmotic strength(OSM)11. *Another polypeptide of Mr ~ 43,000 might be a component of complex A inChlamydomonas44. ‡Sequence analyses indicate that Chlamydomonas IFT74 and IFT72 areencoded by the same gene. Similarly, IFT57 and IFT55 are encoded by the same gene. §TheChlamydomonas homologue of CHE-2, tentatively classified as a complex B protein in C. elegans,has not yet been identified16.



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previously unknown but which had been implicatedin polycystic kidney disease50. The identification ofTg737 as an IFT-particle protein has led to newinsights into the pathogenesis of kidney disease andthe role of kidney primary cilia8,51 (see below).IFT172 is homologous to the rat selective LIMdomain-binding (SLB) protein52, which interactswith a LIM homeodomain transcription factor53.IFT27 is a Ras-like small G protein (H. Qin andJ.L.R., unpublished observations), which indicatesthat it might have a role in coupling extracellular sig-nals to intracellular signalling pathways. IFT52 ishomologous to Ngd5 (REFS 12,36,54), a mouse proteinof unknown function that, in tissue culture cells, isdownregulated by opioid treatment55, which indicates

are resorbed6. By comparing extracts of these fla10-mutant flagella with those of wild-type cells on sucrosegradients and gel filtration columns, it was possible todetermine which flagellar polypeptides make up theIFT particles. IFT particles were found to sediment at~16 S in sucrose gradients and to be composed of atleast 16 polypeptides12,48 that occur in two complexes,which are known as complex A and complex B (TABLE 1).Complex A contains at least 4 polypeptides of rela-tively high molecular weight (M

r= 122–144K),

whereas complex B contains at least 12 mostly lowermolecular weight polypeptides12 (M

r< 100K). That

these proteins are components of the IFT particle wasconfirmed by analysis of LC8-mutant flagella, whichaccumulated both the IFT particles and the IFT-parti-cle polypeptides25.

The amino-acid sequences of many of theChlamydomonas IFT-particle proteins have now beenpredicted from their cDNA sequences8,22,36 (D. G.Cole, G. J. Pazour, H. Qin, J.L.R. and G.B.W., unpub-lished results). Database searches show that virtuallyall of these proteins have homologues in many otherciliated organisms, including the nematode C. elegans(TABLE 1; BOX 2), the fruitfly Drosophila melanogaster,mouse and human, but not in organisms that lackcilia, such as yeast and Arabidopsis thaliana. Therefore,IFT seems to be an ancient and conserved process thatis probably necessary for the maintenance and assem-bly of all eukaryotic cilia and flagella. One possibleexception to this is the fully formed mammaliansperm flagellum, the proteins of which are unlikely toundergo turnover. Indeed, although IFT-particle pro-teins are necessary for the formation of mouse spermflagella49, they have not been detected in the matureflagella (J. San Agustin and G.B.W., unpublishedresults).

Some of the predicted amino-acid sequences arenovel, and so provide no clues to the specific func-tions of the individual IFT-particle proteins. However,there are notable exceptions. IFT88 is homologous tothe mouse protein Tg737, the function of which was

MELANOPHORES

Pigmented cells, present in fishand other vertebrates, in whichpigment granules rapidlydisperse or aggregate by movingalong the microtubules thatradiate from the centre of thecells. This causes the skin todarken or lighten, respectively.The movement of granules iscontrolled by neurostimulation,and aggregation is driven bycytoplasmic dynein, whereasdispersion depends on amember of the kinesinsuperfamily.

TRANSITION FIBRES

The fibres that emanate from thedistal end of each of the tripletmicrotubules that comprise theflagellar basal body, and thatattach the basal body to the cellmembrane at the point wherethe cell membrane becomes theflagellar membrane.

Box 2 | Intraflagellar-transport-particle polypeptides in Caenorhabditis elegans

In the nematode Caenorhabditis elegans, there are known mutations in many of the genes encoding the putativehomologues of intraflagellar-transport (IFT)-particle polypeptides and motors. Interestingly, the mutations are in theche, daf, and osm genes, the products of which are required for the formation and function of the sensory cilia. Forexample, osm-1, osm-5, and osm-6 encode homologues of the Chlamydomonas IFT172, IFT88 and IFT52 IFT-particleproteins, daf-10 encodes a homologue of Chlamydomonas IFT122 and che-11 encodes a homologue of ChlamydomonasIFT140. In addition, che-3 encodes the homologue of the Chlamydomonas retrograde IFT motor subunit DHC1b (REFS 13–16). Therefore, IFT is essential for the assembly of non-motile sensory cilia in C. elegans.

It was presumed that, like the Chlamydomonas IFT particles, the IFT polypeptides that are localized in C. eleganssensory cilia move anterogradely and retrogradely in the cilia. This has now been elegantly shown by fusing sequencesthat encode green fluorescent protein (GFP) to either the kinesin-II non-motor subunit (KAP) gene or the IFT-particle-polypeptide genes, transforming these constructs into C. elegans and observing the motility of their products in vivo14,26

(see Online link to the Laboratory of Cell and Computational Biology for a Web video). The rates of movement of theIFT-particle polypeptides and motors were similar to each other, albeit slower than the rates observed for IFT particlesin Chlamydomonas flagella. Recently, additional C. elegans IFT-particle polypeptides that represent both IFT complexesA and B have been tagged with GFP and their motility observed in vivo. Complexes A and B, and the motors that movethem, were all found to translocate at the same rate in the sensory cilia of the worm16.

Figure 3 | Localization of intraflagellar transport particlesin Chlamydomonas. a,b | Immunofluorescence microscopyimages indicating that only a few intraflagellar transport (IFT)particles, which must represent those in transit, are in theChlamydomonas flagellum (a), and that IFT-particle proteinsare localized primarily to the base of the Chlamydomonasflagellum (b) (green fluorescence marks the IFT particles,whereas red fluorescence marks the flagellar or cytoplasmicmicrotubules). c | Immunoelectron microscopy shows that theIFT-particle proteins (arrows mark gold-antibody labelling of anIFT-particle protein) are docked at the ends of ‘transition fibres’that extend from the distal end of the basal body to theplasma membrane at the base of the flagellum. Parts a and bare modified with permission from REF. 36 © (2002) Cell Press.Part c is reproduced with permission from REF. 36 © (2002)Cell Press.

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although the difference in the phenotypes of themutants indicates that the proteins differ in theirimportance. In contrast to the DHC1b mutant, theIFT-particle-protein mutants that form short flagellado not accumulate IFT particles in their flagella.Defects in the C. elegans homologues of IFT88 andIFT52 similarly affect the assembly of the sensory ciliain this worm11,13,16 (TABLE 1; BOX 2).

Isolation of the IFT particles allowed the produc-tion of both monoclonal and polyclonal antibodiesthat recognize specific IFT-particle proteins.Immunofluorescence microscopy using these anti-bodies, and those prepared against the IFT motors,showed punctate staining along the flagella (FIG. 3a),which presumably represents IFT particles in transit.However, the principal localization of both the IFT-particle polypeptides and the kinesin and dyneinmotors was in a circular pattern around the two basalbodies7,12 (FIG. 3b). This was somewhat surprising,because mobile IFT particles had been observed onlyin the flagella by DIC microscopy, and the lineararrays of IFT particles had been observed only in theflagella by EM.

To learn more about this peri-basal-body distribu-tion of IFT-particle proteins, studies were carried outusing gold-labelled antibodies and thin sections ofmaterial36. These higher-resolution studies showedthat the IFT proteins were localized at the ‘flagellar’end of the basal bodies, specifically on the membrane-associated ends of the transition fibres that connectthe basal body to the cell membrane58,59 (FIG. 3c). Thesefibres demarcate the boundary between the cytoplas-mic and flagellar ‘compartments’, and might representboth a loading zone where cargo that is bound for theflagellum becomes associated with the IFT particlesand a site where the targeting sequences on proteinsthat are destined for the flagellar compartment arerecognized (see BOX 3 and below).

Targeting to the flagellar compartmentCiliary and flagellar membranes contain proteins thatare located specifically on the cilium or flagellum51,60,61.Therefore, a mechanism must exist for the sorting andtargeting of these proteins to the ciliary or flagellarmembrane. Indeed, flagellar ‘targeting’ signals that arerequired for the movement of proteins from their siteof synthesis on cytoplasmic ribosomes to flagellarmembranes have now been shown in Trypanosomaand Leishmania (for a review, see REF. 62). The specificflagellar membrane form of the glucose transporter inLeishmania requires an amino-terminal leadersequence of 30 amino acids to reach its flagellar site.When a chimeric polypeptide was made of the amino-terminal portion of this glucose transporter and a non-flagellar membrane hexose transporter, the latter wastargeted to the flagellar membrane63,64. Similarly, instudies of the targeting of an EF-HAND calcium-bindingprotein to Trypanosoma flagellar membranes, it wasshown that a specific consensus sequence, which wasmyristolated and palmitoylated, was required for fla-gellar membrane localization65.

a connection to opioid-receptor function. IFT57 is aclose homologue of the human protein HIPPI, whichis reported to be involved in the pathogenesis ofHuntington disease56. Further work will be necessaryto determine if the SLB protein, Ngd5 and HIPPI aretrue functional homologues of the IFT-particle pro-teins, and, if so, to understand the connection betweenIFT and the cellular processes with which these pro-teins have been associated.

The importance of specific IFT-particle polypep-tides in flagellar assembly has been shown by the iden-tification of Chlamydomonas insertional mutants thatlack the genes encoding IFT88, IFT57 and IFT52 (REFS

8,36,54,57). These mutants grow and divide normally,which shows that these IFT-particle proteins are notinvolved in any essential processes in Chlamydomonas.However, the IFT88 and IFT52 mutants fail to assem-ble flagella, whereas the IFT57 mutant assembles onlyvery short flagella. So, these specific IFT-particle pro-teins are required for formation of the flagella,

EF-HAND

A graphical description for thestructure of a Ca2+-bindingmotif that was first described inparvalbumin.

Box 3 | A flagellar pore complex?

Although the flagellum is ostensibly ‘open’ to the cytoplasm, it seems that only a subset ofcytoplasmic proteins (the ‘flagellar’ proteins) gain admission to the flagellarcompartment. The boundary between the cytoplasmic and flagellar compartments isdemarcated by ‘transition fibres’, which extend from the distal end of the basal body (seefigure) and connect each of the nine basal-body triplet microtubules to the flagellarmembrane. These transition fibres might be structural components of a ‘flagellar porecomplex’ (FPC) that controls the movement of molecules and particles between thecytoplasmic and flagellar compartments, much as the nuclear pore controls movementbetween the cytoplasmic and nuclear compartments. Immunoelectron microscopy hasshown that the transition fibres are docking sites for the IFT-particle proteins at the baseof the flagellum (see FIG. 3c legend)36. Therefore, we propose that the flagellar membraneproteins and axonemal proteins that are synthesized in the cytoplasm are transported tothe base of the flagellum, where they are recognized by IFT-particle proteins and usheredthrough the FPC into the flagellar compartment. Transition fibres are present inassociation with all basal bodies, so it is expected that all cilia and flagella have an FPCthat functions as a gateway for the admission of specific proteins to the cilium orflagellum. If access to the flagellar compartment is controlled, then we would predict thatpre-assembled flagellar structures, such as radial spokes69 and dyneins arms68, either haveflagellar localization signals on one or more of their constituent polypeptides, or areescorted through the pore by a carrier — perhaps the IFT particles or motors — withwhich they associate.

Centriole/basal body

Cell membrane

Flagellar membrane

Flagellum

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Cross-sections



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the basal body and the flagellum (FIG. 4). This site ofvesicle exocytosis was shown clearly in early studiesthat detailed how mastigonemes — filamentousstructures that extend from the surface of the flagellaof some PROTISTS — become associated with the flagel-lar membrane66. These filaments were observed insidethe vesicles as the vesicles traversed from the Golgi tothe cell surface at a point just adjacent to the basalbody transition region. Similarly, vesicles containingrhodopsin that is destined for the rod outer segmentdock near the base of the connecting cilium in verte-brate photoreceptor cells67. We speculate that individ-ual IFT proteins might cycle back in the endomem-brane system, assist in the sorting of flagellar-boundproteins into specific vesicles, and then target thesevesicles to the docking site at the base of the flagellum.Other components of the IFT system then recognizethe targeting IFT protein and/or the flagellar-boundmembrane proteins and transfer them into the flagel-lar compartment. Peripheral proteins on the outersurface of the membrane would be linked to the IFTsystem through transmembrane proteins and thensimilarly moved into the flagellum. Once inside theflagellum, the membrane proteins are moved distallyalong the flagellar shaft by IFT, as indicated by theobservation that IFT particles remain linked to theflagellar membrane even in distal parts of the flagel-lum6,24,25. Axonemal precursors might be transportedinto the flagellum and along the flagellar shaft as aresult of a direct connection to the IFT system, or byassociation with flagellar membrane proteins that aretransported by IFT.

The molecular basis for targeting membrane andaxonemal proteins to the flagellar compartment ispresumably dependent on targeting sequences eitherin the flagellar polypeptides themselves (as alreadyshown in trypanosomes), or in those proteins withwhich the polypeptides are associated as pre-assemblycomplexes in the cytoplasm. It is now clear that partsof the axoneme — for example, the outer dyneinarms68 and the radial spokes69 are pre-assembled inthe cytoplasm. So, only one polypeptide of the pre-assembly complex would be required to target theentire complex; flagellar proteins that lack the flagellartargeting sequences would be carried into the flagel-lum by associating with proteins that do have suchsequences.

Intraflagellar transport in physiology and diseasePolycystic kidney disease. The mammalian homo-logue of the Chlamydomonas IFT-particle proteinIFT88, known as Tg737 in mouse and human, is ofparticular interest, because an insertional mutation inthe gene encoding this protein causes autosomal-recessive polycystic kidney disease (ARPKD) inmice50. In both mice and humans, ARPKD involvesthe altered differentiation and proliferation of theepithelial cells in the collecting ducts and tubules ofthe kidney, which leads to the formation of numerouscysts50,70. In humans, ARPKD affects up to 1 in 10,000newborns, and ~50 % die within a few weeks of

It is presumed that flagellar integral membraneproteins are synthesized on the rough endoplasmicreticulum, pass through the Golgi apparatus, and arethen transported by post-Golgi vesicles to a vesicle-docking site that is near the transition region between

PROTISTS

Unicellular eukaryoticorganisms, including algae andprotozoans.

Figure 4 | Postulated roles of intraflagellar-transport-particle proteins in targetingproteins to the flagellar compartment. There is clear evidence that flagellar membrane proteinsare carried by vesicles from the Golgi apparatus to the base of the flagellum, where they fuse withthe plasma membrane of the cell66,67. In this figure, it is proposed that proteins destined for theflagellar membrane are sorted into specific vesicles that are then targeted to the base of theflagellum. This sorting and targeting might be accomplished by one or more intraflagellar-transport(IFT)-particle proteins that cycle from the base of the flagellum back through the endomembranesystem, where they become associated with the proteins that are destined for the flagellarmembrane. Once the vesicle is exocytosed, the IFT-particle proteins, with attached flagellarmembrane proteins, become incorporated into IFT particles and are moved through the flagellarpore (the transition fibres) into the flagellar compartment. It is also proposed that non-membraneflagellar proteins — for example, axonemal precursors — are similarly transported, as a result of adirect or indirect association with the IFT particles.

Golgi

Flagellarmembrane

Transition fibre andflagellar pore

Array ofIFT particles

Cell membrane

Basal body

IFT particle Integral cell body membrane protein

Integral flagellar membrane protein

Axonemal precursor

Microtubule

Heterotrimeric kinesin-II

Cytoplasmic dynein 1b

Cytoplasmic dynein 1a



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although the symptoms might not be clinically appar-ent until the patient reaches middle age70. The pri-mary defects in the most common forms of ADPKDare in the genes encoding polycystin-1 and polycystin-2. Polycystin-1 is an integral membrane protein thatinteracts directly with polycystin-2, a calcium-selec-tive cation channel. This complex probably acts in asensory signalling pathway that controls cell differen-tiation and proliferation74–76. But, how is polycystickidney disease that is caused by defects in the poly-cystins related to that caused by defects in the kidneyprimary cilia?

A clue to the answer to this question was providedby a report showing that the C. elegans homologues ofthe vertebrate polycystins are located on the worm’ssensory cilia77, where they also seem to be involved insignal transduction. More recent work indicates that,likewise, mammalian polycystin-1 and polycystin-2are located principally on the ciliary membrane51,78.Therefore, polycystin-1 and polycystin-2 normallyfunction on kidney primary cilia, and mutations thataffect the cilium — either by altering the ciliary poly-cystins or by preventing normal ciliary assembly —lead to polycystic kidney disease.

Until recently, the function of the primary ciliumwas unknown79. However, the localization of the poly-cystins indicates strongly that the kidney primary cil-ium is a sensory organelle that initiates a signal trans-duction pathway that controls cell differentiation andproliferation. In addition, it was shown recently thatwhen kidney primary cilia are bent, they initiate a Ca2+

signal that spreads throughout the cell80, which sup-ports the hypothesis that these cilia are mechanore-ceptors that monitor the rate of fluid flow through thecollecting ducts and tubules81. It will be very interest-ing to determine if the polycystin Ca2+ channels gener-ate this mechanically induced Ca2+ signal. In any case,these results, together with the previous finding thatthe SOMATOSTATIN RECEPTOR 3 is localized specifically toprimary cilia in the brain61, indicate that primary ciliain general might function as cell ‘antennae’ thatreceive various signals and relay them to the cell.

Retinal degenerative disease. Cilia, or structuresderived from cilia, are also involved in the develop-ment and function of several sensory structures in thevertebrate body — for example, in the retina, theinner ear and the nasal epithelium. As IFT probablyoccurs in all cilia and flagella, it is likely to be impor-tant for the assembly and maintenance of these sen-sory structures and tissues as well. The role of IFT hasbeen examined most closely in the outer segments ofthe retinal rod and cone cells (FIG. 6). These light-sen-sory dendritic structures, which contain the photopig-ments and light-transducing machinery, are initiallyformed from primary cilia82,83; a short ‘9+0’ ‘connect-ing cilium’ remains in the adult as the only path ofcommunication between the outer segment and theinner segment84,85, which is where protein synthesisoccurs. After its formation, the rod outer segment iscontinuously turned over at a high rate; it is estimated

birth71,72. In addition, ARPKD might be responsiblefor ~1 in 3,000 prenatal deaths and stillbirths.

Although the kidney lacks motile cilia, many of theepithelial cells of the kidney’s collecting ducts andtubules have a single, non-motile ‘9+0’ cilium, calledthe primary cilium (FIG. 5a; BOX 1). Primary cilia are, infact, present on most cells in the body (see Online linkto Where Are Primary Cilia Found? for a comprehen-sive list of cells that have primary cilia), but in the kid-ney they are particularly well developed. The fact thatIFT88 is essential for flagellar formation inChlamydomonas (see above) indicated that Tg737might be important for formation of the primary ciliain the kidney. Indeed, when kidneys of mice that arehomozygous for the Tg737 insertional mutation wereexamined by scanning EM, they were found to bedefective in ciliary assembly8 (FIG. 5b). Whereas wild-type mice had cilia that extend several micrometresinto the lumens of the collecting ducts and tubules,the mutant had only short stubs of cilia, as is the casefor the Chlamydomonas IFT88 deletion mutant. Theseresults indicated that the primary cause of ARPKD inthe mutant mouse is a failure to assemble the primarycilium owing to a defect in an IFT-particle protein.Subsequent studies have shown that the Tg737 proteinis concentrated at the base of the kidney cilia73, just asthe IFT-particle proteins are located at the base of theflagellum of Chlamydomonas, and that GFP-taggedTg737 moves anterogradely and retrogradely in thecilia of wild-type kidney cells in culture (G. J. Pazour,unpublished results). However, an understanding ofwhy defects in the kidney primary cilium should causepolycystic kidney disease required additional informa-tion that came from studying a related renal disease —autosomal-dominant polycystic kidney disease(ADPKD).

ADPKD affects up to 1 in 500 individuals and, likeARPKD, results in the formation of renal cysts,

Figure 5 | A defect in an intraflagellar-transport-particle protein prevents assembly ofkidney primary cilia. a | Scanning electron micrograph that shows primary cilia (arrows) on theepithelial cells of a collecting tubule from a wild-type mouse kidney. b | The primary cilia occuronly as short stubs (arrows) on the collecting tubule cells of a kidney from a mouse homozygousfor an insertional mutation in the gene encoding Tg737. Tg737 is the mammalian homologue ofthe Chlamydomonas intraflagellar-transport (IFT)-particle protein IFT88. Reproduced withpermission from REF. 8 © (2002) Rockefeller University Press.

a +/+ b –/–

SOMATOSTATIN RECEPTOR 3

One of at least five distinct G-protein-coupled receptors thatbind somatostatin in mammals.



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the gene knockout on photoreceptor-cell mainte-nance could not be excluded.

More recently, immunofluorescence microscopyhas shown that several IFT-particle proteins are con-centrated at the proximal ends, and to a lesser extentat the distal ends, of the connecting cilia of the mouserod22 — a distribution that is remarkably similar tothat seen for IFT-particle proteins in Chlamydomonas.Moreover, in mice that are homozygous for the inser-tional mutation in the gene encoding the IFT-particleprotein Tg737, the rod outer segments develop abnor-mally and eventually degenerate, which leads to acomplete disappearance of the rod cells22. These latterresults provide strong and independent evidence thatIFT occurs in the connecting cilium, and that it isimportant in assembling and maintaining the rodouter segment, presumably by transporting essentialproteins from the inner segment to the outer seg-ment. The degeneration of rod cells that results fromdefects in IFT-motor and -particle proteins is very

that ~2,000 opsin molecules per minute are requiredto maintain the mammalian rod outer segment85, andall of this newly synthesized protein is probably trans-ported to the outer segment through the connectingcilium.

A possible role for IFT in this process was firstindicated by the discovery that the IFT motor kinesin-II is present in the connecting cilia of rods and conesin fish86. Subsequently, Cre-loxP mutagenesis was usedto remove the kinesin-II motor subunit KIF3A specif-ically from the photoreceptor cells of mice21. In theabsence of KIF3A, large quantities of opsin, arrestinand membrane accumulated in the inner segment,and the photoreceptor cells eventually underwentapoptotic cell death. These results implied thatkinesin-II was powering IFT in the connecting cilium,and was required for the assembly and continuedmaintenance of the rod outer segment. However,because kinesin-II might also be involved in othertransport processes in these cells, an indirect effect of

a b

IFT particleMicrotubule

Heterotrimeric kinesin-II

Cytoplasmic dynein 2

Cytoplasmic dynein 1

Inne

r se

gmen

tC

onne

ctin

g ci

lium

Out

er s

egm

ent

(+)

Vesicle

Plus end of microtubule

Outer segmentmembraneprotein

OS

CC

IS

Golgi

(+)(+)

(+)(+)

(+)(+)

Basal bodyFigure 6 | The connecting cilium of the vertebratephotoreceptor cell. a | Electron micrograph showing theconnecting cilium (CC) between the inner segment (IS) and theouter segment (OS) of the vertebrate rod. Image providedcourtesy of J. Deane and J.L.R., Yale University, USA. b | Amodel for intraflagellar transport (IFT) in the vertebrate rod cell.Intracellular vesicles that carry membrane proteins destined forthe outer segment are transported along cytoplasmicmicrotubules to the base of the CC, where they dock and fusewith the cell membrane at the peri-ciliary ridge67 (which might beequivalent to the membrane–transition-fibre junctions seen inFIG. 3c). It is proposed that before, or soon after, docking, themembrane proteins that are on their way to the OS becomeassociated with IFT-particle proteins; they are then transportedby kinesin-II through the flagellar pore complex and distally alongthe microtubules of the CC. When the IFT particles reach thebase of the OS, their cargo of membrane proteins is released toform the membrane discs that are the sites of photoreception.The IFT particles are then transported by cytoplasmic dynein2/1b back down the CC to the peri-basal-body region. Modified with permission from REF. 22 © (2002) RockefellerUniversity Press.



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in the mouse, like its homologue IFT88 inChlamydomonas, is essential for cilia formation. As isthe case for the connecting cilium, the small amountof normal Tg737 protein (or the shorter isoform)expressed in the original insertional-mutant mousemust be sufficient to allow nodal-cilia formation andnormal embryogenesis to take place. We have alsoobserved that respiratory cilia are relatively unaffectedin the original Tg737 insertional-mutant mouse (G. J.Pazour and G.B.W., unpublished results). We can inferthat some cilia or structures derived from cilia — forexample, kidney primary cilia and rod outer segments— are more sensitive to reduced or altered IFT thanother cilia, such as nodal cilia and respiratory cilia.

Human-disease syndromes. The above studies of miceshowed that defects in IFT affect the cilia in severalorgans, which leads to a pleiotrophic phenotype.Similarly, defects in IFT would be expected to affectseveral organ systems — including the kidney and theeye — in humans. It is therefore of interest that thereare several human syndromes — for example,Senior–Loken syndrome, Jeune syndrome andBardet–Biedl syndrome — that are characterized byboth cystic kidneys and retinal degeneration, whichare often found in combination with skeletal defectsor other abnormalities that might also be caused bydefects in cilia87. The genes encoding IFT proteins arepromising candidate disease genes for these humandisorders.

Maintenance and control of flagellar lengthAs discussed above, IFT is required for both theassembly and the maintenance of the flagellum.Axonemes of flagella have long been thought to behighly stable, so why is IFT needed for the mainte-nance of fully formed flagella? Recent results indicatethat, in fact, axonemes do undergo considerable pro-tein exchange89,90. Indeed, the plus (distal) ends of theflagellar microtubules are continuously turned overand require a constant supply of flagellar precursors tomaintain flagellar length91. IFT supplies these precur-sors — if IFT is inhibited by shifting Chlamydomonasfla10ts mutant cells to the restrictive temperature, theflagella shorten at the rate that is expected on the basisof the rate of TUBULIN turnover at the flagellar tip underpermissive conditions91. It is probable that IFT simi-larly supplies the components that are necessary tobuild the new flagellar membrane during flagellargrowth and to replace those membrane componentsthat are known to turn over at a high rate in the fullyformed flagellum92–94. Replacement of membranecomponents might be the main function of IFT in themature retina, where the membranous rod and coneouter segments turn over rapidly (see above).

The discovery that the axoneme undergoes contin-uous turnover indicates that the length of the fullyformed flagellum might be determined by a balancebetween the rate of disassembly at the flagellar tip andthe rate at which replacement axonemal precursorsare delivered to the tip by IFT. Evidence in support of

similar to that observed in retinitis pigmentosa andother human diseases that cause progressiveblindness87,88.

Embryogenesis: left–right-axis determination. Asnoted above, deletion of the IFT88 gene inChlamydomonas completely blocks flagellar assembly.Why, then, are connecting cilia formed in the rod cellsof a mouse that is homozygous for an insertionalmutation in the IFT88 homologue, Tg737 ? TheTg737 insertional allele, known as Tg737 orpk, that wasused in the above studies is a hypomorphic allele —that is, it expresses a greatly reduced amount of nor-mal-length Tg737 messenger RNA50 and Tg737 pro-tein73. It also expresses an elevated amount of ashorter isoform of the Tg737 protein73. Apparently,the relatively small amount of normal-length productand/or the shorter isoform is sufficient to support theassembly of the connecting cilium, but is not ade-quate for full development and long-term mainte-nance of the outer segment. Interestingly, completeknockout of the mouse Tg737 gene is embryoniclethal20; the embryos lack nodal cilia and are defectivein left–right-axis determination, which is a hallmarkof defects in the nodal cilia (BOX 4). Therefore, Tg737

TUBULIN

A protein subunit ofmicrotubules.

Box 4 | Defects in intraflagellar transport reveal a role for nodal cilia

Knockouts of intraflagellar-transport (IFT)-motor and -particle proteins in themouse show that one of theearliest roles for cilia in themammalian embryo is in thedevelopment of left–rightasymmetry. This processdepends on the motility ofcilia on the embryonic node— a triangular patch thatoccurs transiently on thesurface of the embryo duringgastrulation. The nodal ciliaresemble primary cilia butthey are unique in that theyhave an unusual twirlingmovement that is not seen inother primary cilia (forQuick-Time video, see online supplementary data for REF. 17). In the absence of the IFTmotor kinesin-II (REFS 17–19) or the IFT-particle protein Tg737 (REF. 20), nodal cilia fail todevelop. In these embryos, the earliest molecular markers of left–right asymmetry, whichare normally expressed only in the left lateral plate mesoderm adjacent to the nodeshortly after development of the nodal cilia, are expressed bilaterally17,18. Subsequently,the embryos undergo random laterality of heart looping, so that in half of the embryosthe heart is on the wrong side of the midline. This condition is known as situs inversusand is frequently observed in humans with defects in cilia function101. It has beenproposed that the twirling movement of the nodal cilia sets up a gradient of a morphogenin the extra-embryonic fluid across the node, which results in left–right axisdetermination102,103 (see figure). In support of such a role, the embryos of mice with adefect in left–right dynein, which might be the motor that powers nodal-cilia movement,have non-motile nodal cilia and situs inversus102,103, and an artificial fluid flow across thenode of the mutant embryos can restore normal left–right patterning104.

Hypotheticalmorphogen

Nodalcilium

Embryonic node (ventral view)



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cells of the kidney tubule (see above), and in trans-porting somatostatin-generated signals from primarycilia in the mammalian brain61. Other roles for IFT inthe delivery of signals from the cilium to the cell bodywill probably be identified as the functions of the pri-mary cilia become better understood. Such signalscould be transported either as proteins that becomeIFT cargo when activated, or as post-translationalmodifications that occur directly on IFT-particle pro-teins as one step in the signal transduction pathway.

Conclusion and perspectiveIFT was discovered originally as a result of basicresearch on the flagella of the biflagellated green algaChlamydomonas reinhardtii. As the specific genes andproteins involved in IFT were identified, it becamepossible, for the first time, to control the assembly offlagella and cilia, by manipulating IFT inChlamydomonas, C. elegans and mice. This has led to ahost of new insights into the roles of cilia and flagella,including the possible functions of the nearly ubiqui-tous primary cilium, the mechanism for the develop-ment of left–right asymmetry in mammals, and theaetiology of some important human diseases. Thecontinuing investigation of the dynamic process ofIFT in cilia and flagella promises to reveal moresecrets that are hidden in these important, but oftenoverlooked, cell organelles.

this idea has come from experiments showing thatChlamydomonas fla10 ts cells that are maintained atintermediate temperatures, at which the anterogradeIFT motor kinesin-II is partially active, have interme-diate-length flagella91. So, it is possible that IFT has adirect role in the control of flagellar length. For exam-ple, the resorption of flagella before cell division couldbe induced by shutting down IFT.

Carrying signals to and from the flagellumIFT might also have a role in the transport of signalsfrom the flagellum to the cell body and vice versa.During mating, Chlamydomonas cells of oppositemating types first adhere to each other by theirflagella95. As a result of this flagellar adhesion, signalsare sent from the flagella to the cell body to initiate‘gamete activation’ — a complex series of events thatlead to cell fusion and zygote formation. After cellfusion, signals are sent from the cell body to the flagel-lum to inactivate flagellar adhesion. Some of these sig-nals might be transported by IFT. Indeed, shiftingfla10 ts cells to the restrictive temperature blocksgamete activation96. Moreover, a newly discoveredprotein kinase that is moved to the flagellum duringgamete activation97 is reported to be a cargo ofkinesin-II (REF. 98). It is possible that IFT might have asimilar role in moving polycystin-generated signalsfrom the primary cilium to the cell body in epithelial

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AcknowledgementsThis work was supported by National Institutes of Health grants(J.L.R. and G.B.W.), and by The Robert W. Booth Fund at theGreater Worcester Community Foundation (G.B.W.).

Online links

DATABASESThe following terms in this article are linked online to:Entrez: http://www.ncbi.nlm.nih.gov/Entrez/FLA10 | IFT52 | IFT88 | LC8OMIM: http://www.ncbi.nlm.nih.gov/Omim/autosomal-dominant polycystic kidney disease | autosomal-recessive polycystic kidney disease | Bardet–Biedl syndrome |Huntington disease | Jeune syndrome | retinitis pigmentosa |Senior–Loken syndrome

Swissprot: http://www.expasy.ch/Dhc1 | DHC1a | DHC1b | Dhc2 | GFP | HIPPI | KIF3A | KIF3B | Ngd5 | polycystin-1 | polycystin-2 | SLB | Tg737WormBase: http://www.wormbase.org/che-3 | che-11 | daf-10 | osm-1 | osm-5 | osm-6

FURTHER INFORMATIONRosenbaum Lab Research Summary:http://www.yale.edu/rosenbaum/rosen_research.htmlWhere Are Primary Cilia Found?:http://members.global2000.net/bowser/cilialist.htmlPrimary Cilium Resource Page:http://www.wadsworth.org/BMS/SCBlinks/cilia1.htmlLaboratory of Cell and Computational Biology:http://www.mcb.ucdavis.edu/faculty-labs/scholey/Access to this interactive links box is free online.


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