Role of Primary Cilia in the Pathogenesis of Polycystic Kidney Disease
Bradley K. Yoder
Department of Cell Biology, University of Alabama at Birmingham, Birmingham, Alabama
Address correspondence to: Dr. Bradley K. Yoder, Department of Cell Biology, 1918 University Boulevard, MCLM 688, Birmingham, AL 35294-0005. Phone: 205-934-0994; Fax: 205-934-0950; E-mail: byoder{at}uab.edu
Cysts in the kidney are among the most common inherited humanpathologies, and recent research has uncovered that a defectin cilia-mediated signaling activity is a key factor that leadsto cyst formation. The cilium is a microtubule-based organellethat is found on most cells in the mammalian body. Multipleproteins whose functions are disrupted in cystic diseases havenow been localized to the cilium or at the basal body at thebase of the cilium. Current data indicate that the cilium canfunction as a mechanosensor to detect fluid flow through thelumen of renal tubules. Flow-mediated deflection of the ciliaaxoneme induces an increase in intracellular calcium and altersgene expression. Alternatively, a recent finding has revealedthat the intraflagellar transport 88/polaris protein, whichis required for cilia assembly, has an additional role in regulatingcell-cycle progression independent of its function in ciliogenesis.Further research directed at understanding the relationshipbetween the cilium, cell-cycle, and cilia-mediated mechanosensationand signaling activity will hopefully provide important insightsinto the mechanisms of renal cyst pathogenesis and lead to betterapproaches for therapeutic intervention.
The formation of renal cysts is common to a number of humansyndromes, including polycystic kidney disease (PKD), Bardet-Biedlsyndrome (BBS), Meckel syndrome, and nephronophthisis (NPHP)(1). Most prevalent among these disorders is PKD, which canbe inherited as a recessive (ARPKD) or dominant trait (ADPKD).In general, the pathogenesis of these disorders has been welldefined; however, the cellular and molecular processes thatunderlie cyst formation and expansion are not understood (2).Through advances in genomics and computational biology and throughresearch in model organisms, many genes that are associatedwith cystic kidney disease syndromes have been identified. Somewhatsurprising, the unifying theme that has emerged is that manyof the proteins that are involved in cystic diseases localizeto the cilium or to the basal body at the base of cilia (3,4)(reviewed in references [2,5–7]).
The cilium is a microtubule-based organelle that first was identifiedmore than a century ago (8); however, until recently, it hassuffered from a severe lack of respect. Mutations that impaircilia formation or its signaling activity have recently beenshown to have severe consequences for development and for postnataltissue physiology (2,9). For example, during development, ciliaare required for proper left–right axis specification,neural tubule closure and patterning, and proper formation ofthe limbs and long bone (10–13). In addition, cilia signalingdefects in postnatal life cause cystic lesions in the liver,pancreas, and kidney and result in hydrocephalus, and they havebeen associated with mental impairment, obesity, and diabetes(reviewed in reference [6]).
Cilia extend from the surface of many eukaryotic cells and canbe either motile or immotile, the latter being referred to asprimary cilia. In mammals, motile cilia are normally found inlarge groups on the apical surface of epithelial cells, suchas those that line the trachea or that are on ependymal cellsof the brain ventricles (Figure 1A). The role of these ciliain processes such as mucous clearance and cerebrospinal fluidmovement is well documented. In contrast, the importance ofthe primary cilium, which is found as a solitary structure,has gone unnoticed despite its presence on nearly every cellin the mammalian body (Figure 1B). The primary cilium comesin a variety of forms that have been modified to respond toa cadre of stimuli. These diverse forms are found on cells ofthe olfactory epithelium; on rods and cones in the retina, oncells of the renal tubule; and on mesenchyme, fibroblasts, andneurons. Recent research has discovered that primary cilia arefar from being a vestigial organelle as once proposed; rather,they function as critical components of signaling pathways thatare involved in chemo-, photo-, and mechanosensation that allowa cell or an organism to interact with and respond efficientlyto its environment. For example, it is now known that ciliaare required for normal responses to hedgehog (Shh and Ihh)and PDGF-A (13–16). In part, this is due to the localizationof transcription factors, kinases, or receptors that are involvedin these pathways in the cilium axoneme. Understanding the multiplefunctions of cilia will provide important insights into a numberof disease states and developmental defects that are associatedwith abnormal regulation of these pathways.
Figure 1. (A) Scanning electron micrograph of motile cilia located on the ependymal cells that line the brain ventricles. Insert shows higher magnification of motile cilia. (B) Immunofluorescence micrograph of primary cilia (green) located on isolated renal tubule. Nuclei are shown in blue. Insert is a scanning electron micrograph looking into a renal tubule. (C) Architecture of cilia (primary and motile) and the basal body. (D) Intraflagellar flagella (ciliary) transport along the axoneme. Anterograde movement of the intraflagellar transport (IFT) particle is mediated by a heterotrimeric kinesin (kinesin-1) complex, whereas retrograde transport is mediated by a cytoplasmic dynein.
Cilia are complex structures and are devoid of ribosomes. Thecell must transport proteins that are required for cilia assembly,sensory perception, and signaling into the cilium, where theybecome integrated into the axoneme. This movement of proteinsalong the cilia axoneme occurs through a microtubule-based conveyingsystem called intraflagellar transport (IFT; Figure 1D) (17)(reviewed in reference [18]). IFT was first identified in Chlamydomonasand was subsequently found to be conserved in other ciliatedeukaryotes (17,19,20). The proteins that are involved in ciliaformation concentrate around the basal bodies, where they assembleinto complexes called IFT particles. These particles are transportedup the cilium by a heterotrimeric kinesin (kinesin-II complex:Kif3a, Kif3b, and KAP) (17). Retrograde transport back to thebasal body is mediated by a cytoplasmic dynein motor protein.One function of the IFT particle is to carry cargo, such asreceptors and channels, and structural proteins into the ciliaaxoneme, as well as to deliver signals that emanate from thecilia into the cytoplasm in response to external environmentalstimuli (21) (reviewed in reference [22]). This was recentlydemonstrated in the case of the transient receptor potentialvanilloid channels OSM-9 and OCR-2 in the cilia of sensory neuronsin C. elegans. By contrast, IFT did not seem to be involvedin movement of PKD-2 in these cilia (23).
The cilium is assembled during interphase of the cell cycleand originates from the basal body. The basal body is composedof nine triplet microtubules that are assembled into an elaboratebarrel-like structure (Figure 1C) (24). The basal body is alsoknown as the centriole that when surrounded by a dense matrix,called the pericentriolar material, forms the centrosome andfunctions as a microtubule organizing center during mitoticdivision. This close association between the cilia and the centrosomehas led to the speculation that the cilium has a role in regulatingthe cell cycle. In other words, as long as the cell has a cilium,it is unable to proceed through mitosis until the cilium isresorbed, freeing up the centrioles for cell division. Thisis supported by the recent association of cilia proteins withcancer and by the proliferative phenotype seen in cystic kidneydiseases that result from disruption of several cilia-localizedproteins (25–29).
Alternatively, recent data have raised the possibility thatthe IFT proteins play a more direct role in regulating proliferationindependent of the cilium. Studies by Robert et al. (30) havedemonstrated that the IFT protein IFT-88/polaris localizes tothe centrioles throughout the cell cycle and that small interferingRNA–mediated knockdown of IFT-88/polaris promotes cell-cycleprogression to the S and G2/M phases with an increase in proliferation.In contrast, overexpression of IFT88/polaris was found to interferewith G1-S transition, leading to apoptotic cell death. Theirdata further revealed that IFT-88/polaris bound to Che-1, anRb-interacting protein that inhibits the growth-suppressingfunction of Rb. Defining how the IFT proteins are involved incell-cycle regulation and the connection with cilia will hopefullyresult in a better understanding of the molecular mechanismthat drives the proliferative phenotype in diseases such asthese renal cystic disorders.
At the distal end of the basal body just before the start ofthe cilia axoneme are the terminal plate and transition fibers(Figure 1C) (24,31) (reviewed in reference [9]). Although littleis known about the composition of these structures, they arethought to function as a gatekeeper to regulate protein entryinto the cilium. Although the cilia membrane is contiguous withthe plasma membrane, its composition is distinct, and proteinentry into the ciliary membrane domain is tightly regulated.Several key signaling proteins have been localized to this organelle,including channels such as transient receptor potential vanilloid4; the cystic kidney disease–associated proteins polycystin-1and -2; and receptors for somatostatin (SSTR-3), serotonin (HT-6),angiopoietin (Tie-1 and Tie-2), hedgehog (smoothened), and PDGF(PDGFR) (32–36). Although the molecular mechanism thatdirects these proteins into the cilia is unknown, the currentmodel predicts that they dock with the terminal plate and transitionfibers and are loaded onto the transport machinery for deliveryinto the cilium. Several studies have identified cilia targetingdomains. This has been done for polycystin-2 and the odorantresponsive cyclic nucleotide-gated channel CNGB1b, both of whichrequire a RVXP motif for cilia localization (37,38). However,analysis of several other cilia transmembrane proteins indicatesthat the RVXP motif is not a universal targeting address (34,37–40).
The typical cilia axoneme that extends from the basal body consistsof nine microtubule doublets. Most motile forms of cilia alsocontain a central pair of microtubules (9 + 2 axoneme) whileprimary immotile cilia lack the central pair (9 + 0 axoneme).The microtubule axoneme serves as a structure for assembly ofassociated protein complexes that regulate the asymmetric glidingof the central doublet microtubules to generate motility. Anotable exception to this association between architecture andmotility is the solitary cilium that is found on cells of theembryonic node (node cilia). The node is an organizing centerthat is required for establishing embryonic body axes duringdevelopment, and loss of these node cilia results in randomizedleft–right body specification.
In addition to the 9 + 0 and 9 + 2 microtubule-based architecturein the axoneme, an elaborate structure can be seen by electronmicroscopy at the tip of many cilia (Figure 1C) (41). Althoughthe importance of this machine remains unknown, the findingthat cilia length is controlled by the addition or removal oftubulin at the cilia tip and that several proteins involvedin transcriptional responses concentrate in this region suggesta role in regulating cilia signaling activity (15,20). Thismay have implications in cystic kidney disease pathogenesisbecause excessively long cilia or the absence of cilia has beenassociated with cyst development (42–45).
Primary Cilia on Renal Epithelium and Cystic Kidney Diseases
In the kidney, primary cilia extend off the apical surface ofthe epithelium into the tubule lumen and are present on mostcells of the nephron (Figure 1B). These cilia were thought tobe of minimal importance for renal development. However, severalstudies in model organisms, some of which paradoxically lackkidneys, led to an increase in clinical and basic research directedat understanding the function of the renal cilium (reviewedin references [2,6,7]).
In one of these studies, Barr and Sternberg (46) revealed thatthe homologs of polycystin-1 and -2, which are involved in thedominant forms of PKD (ADPKD) in humans, localize to cilia ofsensory neurons of C. elegans. This has also been shown forthe human and mouse homologs (35,47). Loss of the polycystinsin C. elegans did not disrupt cilia formation but rather alteredbehavioral responses that require cilia function. At approximatelythe same time, several groups that were working in Chlamydomonas,C. elegans, and mice uncovered that the cystic renal pathologyin the Oak Ridge Polycystic Kidney mouse (Tg737orpk) was dueto mutations in a protein called IFT88 (also known as Tg737,polaris, or OSM-5) (423–44,48). This protein is requiredfor cilia formation and functions as a component of the IFTparticle. The importance of cilia for normal renal functionand in cystogenesis was further supported by disrupting KIF3a(IFT-associated kinesin motor) specifically in the mouse kidneyand by antisense morpholino oligonucleotide–mediated knockdownof IFT gene expression in Zebrafish (49,50).
Although these studies suggest cilia are important for normalmaintenance of renal physiology, the role of the primary ciliumand its relationship to the mechanism of cyst formation remainspoorly defined. Several studies have begun to address this issue.Praetorius and Spring (51,52) demonstrated that renal epitheliumresponds to fluid flow–mediated deflection of the ciliaaxoneme by increasing intracellular Ca2+. This calcium signalis distinct from mechanical stress that is sensed by the plasmamembrane because removal of the cilium abolished the flow response.Furthermore, Nauli et al. (53) revealed that this flow responserequired the function of the polycystins, which localize inthe cilium. Similar defects were reported by Liu et al. (54)in perfused tubules that were isolated from Tg737orpk mutants.Although calcium is a widely known second messenger, the downstreameffects of this signal and the importance for cyst developmentare unknown.
In addition to functioning as a mechanosensor, deflection ofthe cilia axoneme and the polycystins has effects on gene expression(55,56). In the presence of normal flow conditions, polycystin-1remains in the cilia in association with STAT6 and p100. However,under nonflow conditions, the C-terminal tail of polycystin-1is proteolytically cleaved and translocates to the nucleus withSTAT6 to activate the AP-1 pathway (55). As with the calciumresponse, the downstream targets of this translocation eventthat are important in cyst development and renal cell functionare unknown.
Another role of cilia and polycystin-1 was proposed by Shillingfordet al. (57). Their studies found that polycystin-1 functionsto regulate activity of mammalian target of rapamycin (mTOR),a protein with essential roles in protein translation, cellgrowth, and proliferation (58). In cystic epithelium, mTOR activitywas markedly elevated. Furthermore, treatment of rodent PKDmodels with rapamycin, an inhibitor of mTOR, attenuated therenal cystic pathology. According to this model, the disruptionof cilia or mutations in polycystin-1 result in loss of a polycystin-1/mTORinhibitory complex in the cilium, which in turn leads to increasedproliferation and cyst development.
Another model that involves cilia and PKD was proposed by Fischeret al. (59). In these studies, they demonstrated that defectsin fibrocystin, a ciliary protein that is disrupted in humanARPKD, was associated with alteration in the orientation ofthe mitotic spindle relative to the axis of the tubule. Duringnormal tubule growth, the mitotic spindle of dividing cellsaligns with the axis of the nephron; however, in cells withmutations in Pkhd1 (encodes fibrocystin) as well as Hnf-1, thespindle fails to orient correctly. This altered orientationof cellular division results in expansion of the tubule diameter(i.e., cyst formation) rather than increased nephron length.The role that cilia may play in regulating mitotic spindle orientationhas not been fully explored.
Multiple proteins whose functions are disrupted in non-PKD (notaffecting polycystin-1, polycystin-2, or fibrocystin) formsof renal cystic diseases have also been reported in the ciliumor at the basal body at the base of the cilium (reviewed inreferences [60,61]). The function of these proteins with regardto cyst development is still being determined, but, in general,mutations in these proteins do not seem to have major effectson cilia morphology. Included in this class are several of theproteins that are involved in BBS, Meckel syndrome, and NPHP.
BBS is a rare, genetically heterogeneous group of disorderswith a combination of pathologies, including obesity, retinaldystrophy, polydactyly, mental retardation, and cysts in thekidney (BBS [MIM 209900]). Twelve genes (BBS1 through 12) thatare involved in BBS have been identified, and, in many cases,the corresponding proteins have been localized to the ciliaaxoneme or basal body (61–63). In most cases, the functionof the BBS proteins remains elusive; however, analyses of BBS-7and BBS-8 in C. elegans revealed they have a role in regulatingIFT movement along the cilia axoneme (64).
NPHP is also a heterogeneous group of diseases that result frommutations in six or more genes (nphp1 through 6) (65–67).Collectively, the NPHP proteins are referred to as nephrocystins,and data in mammalian systems suggest that they function aspart of a complex. Recently, these proteins were localized tothe cilium or the basal body (68,69). In the case of NPHP-1,this localization depends on its ability to interact with thephosphofurin acidic cluster sorting protein-1, which is regulatedby the phosphorylation of NPHP1 by casein kinase 2 (70).
The function of the NPHP proteins is uncertain, but data suggestthat they are involved in the formation of signaling complexes.In the cases of NPHP-2 (inversin), one function is regulatingthe choice between noncanonical (-catenin independent) and canonical(-catenin dependent) Wnt signaling. In the kidney, canonicalWnt signaling prevails in the developing nephron, whereas noncanonicalsignaling is more important for tubular structure maintenance(71–73). NPHP-2 (inversin) localizes to the cilia/basalbody and seems to function as a molecular switch to downregulatecanonical Wnt signaling (74). Because ectopic activation of-catenin is known to cause cyst formation, it is possible thatdysfunction of NPHP-2 would lead to persistent activation ofthe canonical pathway and thus -catenin–induced cystogenesis(75).
Additional insight into the role of the NPHP proteins has beenderived from simpler model organisms; nphp-1 and nphp-4 homologshave been identified in C. elegans. It is interesting that mutationsin these genes in C. elegans did not disrupt cilia formationbut did cause behavioral defects that are typical of those thatare seen in mutants that lack cilia-mediated signaling activity(67,69). As for the mammalian proteins, the C. elegans NPHPproteins function as part of a complex as evidence by the factthat disruption of NPHP-4 causes the delocalization of NPHP-1from the base of the cilium (69).
Cilia and the Extrarenal Pathologies that Are Associated with PKD
In addition to renal cysts, humans and mouse models of PKD exhibitpathologies in tissues other than the kidney (60,76–78).In human PKD, the most commonly affected tissues are the liverand the pancreas, along with vascular abnormalities that involvebrain aneurysms. Whether these pathologies are caused by cilia-mediatedsignaling defects remains to be fully explored; however, thisseems likely in light of the systemic nature of the diseaseseen in the Tg737orpk hypomorphic mutant (6,79). The partialloss of IFT and cilia function in these mice results in cystformation in the liver along with bile duct hyperplasia andsevere pancreatic defects (80,81).
Although the function of the primary cilium in bile ducts andits relationship to pathologies in PKD is not understood, recentstudies by Masyuk et al. (82) demonstrated that the polycystinslocalize to the primary cilium of cholangiocytes and that thecilium functions as a mechanosensor, as observed in the kidney.They further showed, using microperfused intrahepatic bile ducts,that luminal flow increased intracellular calcium and also repressedcAMP levels. The decrease in cAMP is mediated through calciuminhibition of adenylyl cyclase 6, which is also present in thecilium. These findings are intriguing because intracellularcAMP levels are markedly elevated in cystic renal epitheliumin human PKD as well as in mouse models, in which cilia or polycystinfunction is abrogated (83–86). Furthermore, in contrastto normal renal cells, cAMP acts as a mitogen in PKD epithelium,which can be inhibited by calcium. In addition, reduction ofcAMP levels in cystic kidney disease mouse models using vasopressinreceptor 2 antagonists greatly retards cyst formation or progression(83,86). Together, these findings provide insights into themechanism behind the proliferative phenotype in PKD renal epithelium,where loss of the flow-induced calcium signal and subsequentincrease in cAMP lead to the proliferative response to cAMP(87,88).
Although not a feature of human PKD, defects in the polycystinsin mice also result in developmental abnormalities. Most notableare the random specification of the left–right body axis(situs inversus or heterotaxia) in mice with mutations in pkd-2and skeletal defects in pkd-1 mutants (89,90). These phenotypesare also observed in the IFT mutants such as the Tg737 nullmice (91). One of the current models suggests that polycystin-2,located in the cilia axoneme, is required to sense fluid movementover the surface of the embryonic node, similar to that proposedin the kidney (90,92). This is thought to cause an asymmetriccalcium signal that establishes the left and right body axis.However, it should be noted that several other models have beenput forth to explain the role of cilia in establishing the bodyaxis and that true mechanisms have not yet been firmly established(93,94).
Research conducted during the past decade has led to the discoverythat defects in proteins that localize to cilia or the basalbody are primary contributors to renal cyst development. Furthermore,these studies have uncovered a role for the primary cilium asa mechanosensor in a number of tissues and are providing importantinsights into the molecular and cellular mechanism that leadto cystogenesis. Primary cilia on tubule epithelia are ideallypositioned to receive extracellular stimuli and for transductionof these signals into the cell to elicit responses. The ciliumextends into the lumen of tubules away from the cell's immediatesurface to evaluate changes in the cell's environment. The ciliumalso has a relatively large membrane-to-cytosol ratio that facilitatesclose association among receptors, channels, and the downstreamsignaling machinery in addition to permitting rapid changesin second messenger concentrations. Finally, current data suggestthat protein entry into the cilium is under regulatory control,making this organelle a specialized domain for controlling sensoryresponses.
More recent data have suggested an alterative role for an IFTprotein that is distinct from that in cilia formation. Thesenew findings suggest that the IFT proteins may be directly involvedin regulating cell-cycle progression. Such a role for the IFTproteins could help to explain the proliferative phenotype thatis associated with cystic kidney disorders.
Activities were supported by National Institutes of Health grantRO1 DK65655 (B.K.Y.).
I regret that space limitations prevent me from acknowledgingthe research by many of those who have contributed to the datathat led to the recent renaissance of the cilium. I thank M.Winkelbauer and Drs. Haycraft and Guay-Woodford for criticalcomments and advice on this review.
Footnotes
Published online ahead of print. Publication date availableat www.jasn.org.
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) (32–36). Although the molecular mechanism that directs these proteins into the cilia is unknown, the current model predicts that they dock with the terminal plate and transition fibers and are loaded onto the transport machinery for delivery into the cilium. Several studies have identified cilia targeting domains. This has been done for polycystin-2 and the odorant responsive cyclic nucleotide-gated channel CNGB1b, both of which require a RVXP motif for cilia localization (37,38). However, analysis of several other cilia transmembrane proteins indicates that the RVXP motif is not a universal targeting address (34,37–40). 
, the spindle fails to orient correctly. This altered orientation of cellular division results in expansion of the tubule diameter (i.e., cyst formation) rather than increased nephron length. The role that cilia may play in regulating mitotic spindle orientation has not been fully explored. 
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Abstract
Cystic Kidney Disease