The primary cilium ata glancePeter Satir1,*, Lotte B. Pedersen2

and Søren T. Christensen2

1Department of Anatomy and Structural Biology,Albert Einstein College of Medicine, Bronx, 10461NY, USA2Department of Biology, University of Copenhagen,2100 Copenhagen, Denmark*Author for correspondence (satir@aecom.yu.edu)

Journal of Cell Science 123, 499-503© 2010. Published by The Company of Biologists Ltddoi:10.1242/jcs.050377

This article is part of a Minifocus on cilia and flagella. Forfurther reading, please see related articles: ‘Sensoryreception is an attribute of both primary cilia and motilecilia’ by Robert A. Bloodgood (J. Cell Sci. 123, 505-509),‘The perennial organelle: assembly and disassembly of theprimary cilium’ by E. Scott Seeley and Maxence V. Nachury(J. Cell Sci. 123, 511-518), ‘Flagellar and ciliary beating:the proven and the possible’ by Charles B. Lindemannand Kathleen A. Lesich (J. Cell Sci. 123, 519-528) and‘Molecular mechanisms of protein and lipid targeting tociliary membranes’ by Brian T. Emmer et al. (J. Cell Sci.123, 529-536).

The primary cilium, which was first so namedby Sergei Sorokin (Sorokin, 1968), is a solitaryorganelle that emanates from the cell surface ofmost mammalian cell types during growtharrest. Increasing evidence suggests thatprimary cilia are key coordinators of signalingpathways during development and in tissuehomeostasis and, when defective, are a majorcause of human diseases and developmentaldisorders (now commonly referred to asciliopathies).

Primary cilia consist of an axoneme of ninedoublet microtubules that extends from a basalbody [which is derived from the older (mother)centriole of the centrosome, surrounded by theciliary membrane (a specialized domainextension of the cell membrane)]. Themicrotubule pattern of the ciliary axoneme istraditionally abbreviated by referring to thenumbers of peripheral doublets and single centralmicrotubules as 9+2, 9+0 etc. In contrast to thoseof motile 9+2 cilia, axonemes of non-motile

primary cilia lack key elements involved inciliary motility, including the central pair ofmicrotubules and the proteins that surround them,most if not all radial spokes and, importantly,outer and inner dynein arms that powermicrotubule sliding to produce motility (Satir andChristensen, 2007). Single 9+0 primary cilia arefound on a large number of cells in themammalian body, including stem, epithelial,endothelial, connective-tissue and muscle cellsas well as neurons [for a more detailed list,please see Wheatley (Wheatley, 1982) and thewebsite http://www.bowserlab.org/primarycilia/cilia3.htm]. The 9+0 pattern of the primary ciliumis often lost towards the cilium tip, where doubletmicrotubules end or change position.

Until recently, three hypotheses existedregarding the functional significance of primarycilia: first, that the cilium was vestigial; second,that it provided a means of sequestering thecentriole, so as to inhibit cell division; and third,that it was a cellular sensory structure. The first

499Cell Science at a Glance

(See poster insert)

© Journal of Cell Science 2010 (123, pp. 499-503)

The Primary Cilium at a GlancePeter Satir, Lotte B. Pedersen and Søren T. Christensen

Abbreviations: APC, adenomatous polyposis coli; Ax, axoneme; Dc, distal centriole; Dvl, Dishevelled; ER, endoplasmic reticulum; Erk1/2, extracellular signal-regulated kinase 1/2; G, Golgi; Gli-A, Gli transcription factor (activating form); Gli-R, Gli transcription factor (repressing form); Gsk3β, glycogen synthase kinase-3 β; Hh, Hedgehog; IFM, immunofluorescence microscopy; IFT, intraflagellar transport; LM, light microscopy; Mek1/2, mitogen-activated protein kinase kinase 1/2;

MT, microtubule; NHE1, Na+-H+ exchanger 1; Pc, proximal centriole; Pctn, anti-pericentrin; PC1 and PC2, polycystins 1 and 2; PDGF, platelet-derived growth factor; PDGFRαα, PDGF receptor αα; PM, plasma membrane; Ptc1, Patched 1; SEM, scanning electron microscopy; Smo, Smoothened; Sufu, suppressor of fused; STAT6, signal transducer and activator of transcription 6; tb, acetylated α-tubilin; TCF/LEF, T-cell-specific transcription factor/lymphoid enhancer binding factor.

Primary cilia are single, usually non-motile, organelles that extendfrom most mammalian embryonic and adult differentiated cells,and function as sensory antennae for many normal signal trans-duction pathways. Each primary cilium grows above a basal bodyderived from the older (mother) centriole after cell division andcomprises an axoneme of nine doublet microtubules (withoutthe central pair characteristic of motile cilia), surrounded by theciliary membrane into which specific receptors and channels aretransported. Disruptions of primary cilium formation or signaling leadto ciliopathies, including many human developmental abnormalities.

Proposed ciliary signaling pathways in development and tissue homeostasis

No cilium

Cell migration

Cell-cycle entry

PDGFRα

NHE1 Leading edge

Off On

Mechanosignaling

Non-canonical

Erk1/2

Akt

Mek1/2

FusedSufu

Gli2-R

Gli-R

Gli3-R

Ptc1

Smo

Gli2-A

Gli3-A

Gli-A

Ptc-1

Smo

• Cell proliferation• Cell differentiation

Ca2+

Hh

HhHh

Hh

APC

APC

GSK3β

GSK3β

Inversin

DvlDvl

β-catenin

LRP5/6

Frizzled

Frizzled?

Wnt

Wnt Wnt

• Cell differentiation• Planar cell polarity

Degradationof β-catenin

Axin

Axin

Dvl

PC2

PC1 STAT6p100

STAT6p100

PDGFRαααα signaling Hedgehog (Hh) signaling

Cleavageof PC1

STAT6

Inversin

p100

DvI

Fluid flow

Ca2+ store

NHE1

Nucleus

Ciliopathies

ERGolgi

Receptor

Ligand

Nucleus

Transcriptionof target genes

Centrosome

PM

Examples of ciliopathies

■ Cystic diseases in kidney, pancreas and liver

■ Skeletal patterning defects

■ Anosmia

■ Hydrocephalus, exencephalus

■ Situs inversus

■ Cognitive defects

■ Hyperphagia or obesity

■ Diabetes

■ Retinitis pigmentosa

or blindness

■ Skin diseases

■ Impaired wound healing

■ Cancer

■ Atherosclerosis and hypertension

■ Early embryonic death

Examples of syndromes

■ Kartagener’s syndrome

■ Bardet-Biedl syndrome

■ Meckel-Gruber syndrome

■ von Hippel-Lindau syndrome

■ Senior-Løken syndrome

■ Alström syndrome

■ Usher syndrome

■ Joubert syndrome

■ Ellis-van Creveld syndrome

■ Oro-facial-digital type 1 syndrome

ImmunofluorescenceMTs and primary cilia (arrow) were stained red (anti-acetylatedα-tubulin, tb), centrosomes (asterisks) cyan (anti-pericentrin,Pctn) and DNA blue (DAPI).

Redrawn from Christensen et al., 2008, with permission.

MT

MT

Cell-cycle entryCiliary resorptionand duplicationof centrosomes

Mitosis

Growth arrestCapture of centrosomalmother centriole, centrosomaltranslocation to PM andciliary assembly by IFT

PDGF-AA

PDGF-AA

PDGF-AA

Target

STAT6p100

Cellproliferation

• Cell differentiation• Planar cell polarity

Activates

Inhibits

TCF/LEFβ-catenin

β-cateninβ-catenin

β-catenin

Cellproliferation

Canonical

Wnt signaling

No cilium

Target

Off OnOff On

PDGFRAPDGFRA

NHE1

Target Target Target

TCF/LEF

Target Target

Target

IFT train

Images reproduced, with permission, from Jensen et al., 2004 (A,E), Kiprilov et al., 2008 (C), and Gilula and Satir, 1972 (D).

Axonemal 9+0 MT structure

Ciliary necklace

Distal centrioletransition fibers

Centriole nine-MTtriplet structure

Subdistalappendage

Dc

C

D

E

FB

Cilium

Transition fibersPM

Ant

erog

rade

IFT

Ret

rogr

ade

IFT

Axoneme (9+0)

Vesicle

Distalcentriole

Golgi

IFT particle

Cytoplasmicdynein 2

Cytoplasmicdynein 1

Kinesin 2

Ciliarymembraneprotein

Tubulin

Longitudinal sections of theprimary cilium and the centrioles

Cross-sections of the primarycilium/centriole axis

Reproduced courtesyof Stefan Geimer

Mousefibroblast

Mousefibroblast

Mousefibroblast

tbPctnDAPI

tbPctnDAPI

*

*

* tbPctnDAPI

* *

Mousefolliclegranulosa cell LM

Humanovariansurface epithelium

Humanpancreaticductepithelialcell

SEM

1 2 43tb

DAPI

tbcentrin

DAPItb

Humanembryonic

stem cell

A

Ax

G

Ciliarynecklace

Transitionfibers

Pc

Dc

Ultrastructure Ciliary assembly and maintenance by IFT

What are primary cilia? Formation and resorption of the primary cilium

Primary cilia in diverse cell types (arrows). 1-3: primary cilia visualized by LM or stained with anti-acetylated α-tubulin for IFM. Centrin marks centrioles. Images courtesy of Stefan C. Teilmann (1,2) and Sonja K. Nielsen (3). 4: SEM image of a primary cilium, reproduced from Kiprilov et al., 2008, with permission.

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hypothesis has been falsified by experiment. Inone sense, the second hypothesis is correct – thatis, the majority of cells that have primary ciliaare non-cycling differentiated cells or stem cellsin G0. The primary cilium is resorbed in cellsthat re-enter the cell cycle and divide, only togrow again on each daughter cell as the cellsonce again become quiescent (summarized inthe poster). In addition, it is now clear that thethird hypothesis is accurate: a major function ofprimary cilia is in cell signaling, because avariety of receptors, ion channels andtransporter proteins, as well as some of theirdownstream effector molecules, localize to thecilium or basal body. Signaling in the ciliumcoordinates key processes during developmentand in tissue homeostasis, including cellmigration, differentiation and/or re-entry intothe cell cycle, specification of the plane of celldivision, and apoptosis. Sensory modalities towhich the primary cilium responds includemechanical stimulation (bending of thecilium) and chemosensation (detection of aspecific ligand, growth factor, hormone ormorphogen). In some specialized cases, primarycilia can also respond to light (Insinna andBesharse, 2008), temperature (Kuhara et al.,2008), osmolality (Christensen et al., 2005) orgravity (Moorman and Schorr, 2008) (note,however, that the ‘stereocilia’ of hair cells ofthe ear, which respond to mechanicaldisplacement, are microvilli, not primary cilia).In invertebrates, including C. elegans andDrosophila, primary cilia form the basisof several types of sense organs or sensilla andare effectively dendritic extensions of specificneurons; in vertebrates, the outer segments ofphotoreceptors are modified primary cilia.

This poster article presents an outline of themechanisms involved in the assembly andfunction of mammalian primary cilia, with afocus on some of the main signaling pathwaysthat are associated with the cilium. In virtuallyevery tissue, a set of specific receptors becomeslocalized to the ciliary membrane of the primarycilium to detect particular environmentalsignals. As indicated in the poster, thesubsequent cascade within the cell influencesthe pattern of gene expression and potentialphysiological responses.

IFT builds primary ciliaTo build a primary cilium, the centrosomemigrates towards the cell surface as a cell entersG0. The mother centriole attaches to a Golgi-derived vesicle that then expands, with theaxoneme of the primary cilium growing abovethe centriole within the ciliary membrane, whichprojects into the vesicle lumen (Sorokin, 1962).The axonemal microtubules polymerize at thegrowing tip of the projection, to which cargo is

delivered by intraflagellar transport (IFT; seebelow). The vesicle is eventually exocytosed toexpose the primary cilium at the cell surface,where ciliary growth continues for up to severalmicrometers to form the mature cilium. Thedocking of the mother centriole to the Golgi-derived membrane is thought to be mediatedin part by the distal appendages of thecentriole, also known as transition fibers, andthe original attachment point to the membraneprobably corresponds to the region known asthe ciliary necklace (Gilula and Satir, 1972), theproposed barrier between the ciliary membraneand the general cell membrane. The transitionfibers and necklace are thought to be part of a‘ciliary pore complex’ through which onlyselected proteins are allowed passage into theciliary compartment (Rosenbaum and Witman,2002).

IFT is an evolutionarily conserved motilityprocess that is required for growth andmaintenance of both motile and primary cilia(Rosenbaum and Witman, 2002). IFT relies onthe association of ciliary building blocks (e.g.tubulin, radial-spoke proteins and peripheralmembrane proteins such as guanine-nucleotideexchange factors) with a scaffold of IFT-particleprotein complexes, the components of which areorthologous from Chlamydomonas reinhardtiito humans. The IFT particles and theirassociated cargo proteins are transported alongaxonemal microtubules by kinesin 2 motorproteins in the anterograde (base-to-tip)direction, after which cargo is delivered to thegrowing tip, and by cytoplasmic dynein 2 in theretrograde (tip-to-base) direction. The process isschematized in the accompanying poster. Otherreviews on IFT have been published recently(Cole and Snell, 2009; Pedersen andRosenbaum, 2008).

Primary-cilium defects lead to kidneydiseaseThe significance of primary cilia in signalingbecame clear on examination of a hypomorphicmouse mutant (Tg737orpk RpW) (Lehman et al.,2008) that was deficient in the homolog ofIFT88, a Chlamydomonas IFT protein (Pazouret al., 2000). The mouse mutant had beendeveloped as a model for human autosomalrecessive polycystic kidney disease (ARPKD),because the mice developed polycystic kidneysand many other pleiomorphic phenotypes beforedying a few days after birth. Just as in aChlamydomonas Ift88 mutant, primary cilia didnot grow normally in kidney cells (andelsewhere) in the mutant mouse. It was proposedthat polycystic kidneys developed becauseprimary-cilium signaling was defective. Thiswas confirmed when the polycystins 1 and 2(PC1 and PC2, respectively) – which form a

TRP Ca2+ channel protein complex and aredefective in models for autosomal dominantpolycystic kidney disease (ADPKD) – werefound to be normally localized to the primarycilium (Pazour et al., 2002; Yoder et al., 2002),but were mislocalized or absent when ADPKDdeveloped. Meanwhile, Praetorius and Springdemonstrated that the kidney primary ciliumacts as a flow sensor; when the cilium is bent,Ca2+ enters the cell as a messenger molecule(Praetorius and Spring, 2001). Thismechanoregulation of intracellular Ca2+ isimpaired in the mutant mouse kidney (Liu et al.,2005). Ciliary mechanoregulation appears not tobe limited to kidney epithelial cells, but mightoperate in a variety of cell types and tissues,either in response to fluid flow, such as on theembryonic node (McGrath et al., 2003),endothelial cells (Iomini et al., 2004; Nauli et al.,2008; AbouAlaiwi et al., 2009; Hierck et al.,2008) and cholangiocytes (Masyuk et al., 2006),or through direct interaction between theprimary cilium and the extracellular matrix(ECM), such as in chondrocytes (McGlashan etal., 2006) and smooth muscle cells (Lu et al.,2008).

Analysis of mutants such as the Tg737orpk RpW

mouse has indicated that signaling through theprimary cilium is essential for normaldevelopment and function, not only of thekidney, but also of many other tissues andorgans. Consequently, ciliary dysfunction mightlead to an array of developmental abnormalitiesand diseases (ciliopathies), includingrandomization of the left-right body axis,abnormalities in neural-tube closure andpatterning, skeletal defects, cystic diseases,blindness, behavioral and cognitive defects, andobesity (Lehman et al., 2008; Quinlan et al.,2008; Veland et al., 2009). An overview ofciliopathies and syndromes caused by defects inassembly or function of primary cilia ispresented in the poster.

Orientation of primary ciliaAt first glance, the primary cilium appears to beradially symmetrical, with each microtubuledoublet equivalent to every other doublet;however, this is probably not the case because,in motile cilia, every doublet can be specificallynumbered with respect to the effective stroke,whose direction (arbitrarily defined as cellularleft) is identified by a basal foot. Similarly tomotile cilia, primary cilia often have a basal foot(Wheatley, 1982) but, with or without thisstructure, basal bodies and primary ciliaseemingly ‘know’ left from right (Bell et al.,2008). In conjunction with other factors,orientation of the basal body, and thereforeorientation of cilia, translates into left-right cellorientation and nodal flow and then to body-axis

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determination at the embryonic node (Hirokawaet al., 2006). In a flow gradient (as in the kidneytubule) or in a chemotactic gradient (as infibroblast migration during wound healing)(Christensen et al., 2008), all primary cilia alignin a single direction, and cell orientation seemsto be determined by this. In the kidney, thedirection in which the cilia bend with flowdepends on their orientation. The flow, andtherefore the bend, is always in the anterior-posterior direction so the gradient of Ca2+

concentration or other signaling moleculesalong the cellular axes should be identicallydisplayed in the anterior-posterior direction inevery cell. Because the gradient is uniform fromcell to cell, we can probably infer that thisdetermines a consistent anterior-posteriororientation of the mitotic spindle for celldivision. In the migrating fibroblasts at a woundedge, orientation of primary cilia ensures thatthe direction of cell migration is uniform.However, when the primary cilium is missing ordefective, orientation is random, whichtranslates into randomization of left-rightasymmetry in body form, randomization ofmigration direction (Schneider et al., 2010) orrandomization of mitotic-spindle orientation(Fischer et al., 2006).

Diversity and dynamics of signalingpathways in primary ciliaThe signaling pathways coordinated by primarycilia are quite diverse, and depend on the celltype. As indicated in the accompanying poster,the pathways include signaling through Ca2+,receptor tyrosine kinases (RTKs), Hedgehog(Hh), Wingless (Wnt), neuronal and purinergicreceptors, as well as through communicationwith the ECM (Christensen et al., 2007;Christensen et al., 2008; Eggenschwiler andAnderson, 2007; Kiprilov et al., 2008; Gerdeset al., 2009; Knight et al., 2009; Masyuk et al.,2008; Praetorius and Leipziger, 2009; Wong andReiter, 2008; Jensen et al., 2004). A singleprimary cilium can be set up for several differentkinds of signaling and can respond, for example,to mechanical strain as well as to severalmorphogens, hormones or growth factors.Different receptors or channels can be present inthe same cilium at the same time or at differenttimes. The diversity and dynamics of importantciliary membrane proteins and their effectormolecules in the cilium-centrosome axis hasonly begun to be catalogued, and the list ofwhich pathways are important for specifictissues, especially during development, is likelyto be expanded in the future.

Primary cilia in adult tissuesSignaling via the primary cilium is of paramountimportance during development, and probably

remains so in stem-cell populations in varioustissues. In the adult, primary cilia might stillfunction in fibroblast cell-cycle control and/orcell migration during tissue regeneration andwound healing (Schneider et al., 2005;Schneider et al., 2009; Schneider et al., 2010).Most other differentiated, non-dividing cells ofthe adult body, including neurons and kidneycells, possess primary cilia. The primary ciliain these tissues might be necessary formaintenance of the differentiated state andsuppression of cyst formation or oncogenesis.Davenport and colleagues used an induciblesystem to disrupt IFT and remove primary ciliafrom all adult mouse tissues or from specifictissues (Davenport et al., 2007). Even whenall tissues were affected, the devastatingabnormalities and lethality seen after embryonicloss of IFT did not occur, although PKDeventually developed after about a year,presumably because cell division was greatlyreduced and cystogenesis in the adult is slow.

In many tissues, aberrant activation orabsence of ciliary signaling is correlated withuncontrolled cell division and cancer(Christensen et al., 2008; Kuehn et al., 2007;Mans et al., 2008; Michaud and Yoder, 2006;Nielsen et al., 2008; Plotnikova et al., 2008;Wong et al., 2009; Han et al., 2009). However,an immediate effect of ciliary removal, either ofall adult primary cilia or specifically of cilia onneurons of the hypothalamus in adult mice, ishyperphagia (compulsive eating), which leadsto obesity. Secondarily, obesity leads to defectsthat resemble type II diabetes. These effects donot occur if the feeding of the knockout mice isrestricted (Davenport et al., 2007). Specifichormone receptors associated with feedingbehavior localize to cilia of the hypothalamus,including somatostatin sst 3 receptor (Sst3R)(Handel et al., 1999) and melanin-concentratinghormone receptor 1 (Mchr1) (Berbari et al.,2008) in neuronal primary cilia, as well as leptinreceptor (LepR) in olfactory cilia (Baly et al.,2007). The Sst3R and Mchr1 receptors aremislocalized in neurons of mice that havemutations in proteins that correspond to thoseobserved in individuals with the syndromicobesity condition Bardet-Biedl syndrome(Berbari et al., 2008; Seo et al., 2009).Furthermore, type 3 adenylyl cyclase, which isalso associated with obesity in mice andhumans, is also specifically localized tohypothalamic neurons (Wang et al., 2009). A‘yin-yang’ relationship, in which activationbetween the ciliary receptors in hypothalamicneurons alternates to stop and start feedingbehavior, might be involved in the satietyresponse (Satir, 2007).

Obesity might also be linked to primary ciliain adipose tissue. Adipogenic differentiation and

fat accumulation is associated with transientformation of the primary cilium, containing Wntand Hh signaling components, such thatadipocytes in culture derived from dermalfibroblasts of individuals with Bardet-Biedlsyndrome exhibit a higher predisposition for fataccumulation and a higher secreted leptin levelthan control cells (Marion et al., 2009). Zhu andcolleagues demonstrated that the primary ciliumand its basal body form an organized signalingpathway for the IGF-1 receptor to induceadipocyte differentiation in confluent 3T3-L1preadipocytes (Zhu et al., 2009). In addition,childhood obesity and type II diabetes inAlström syndrome patients is caused bymutations in Alström syndrome 1 protein(ALMS1), which localizes to the base ofprimary cilia (Hearn et al., 2005) and isregulated during adipogenesis (Romano et al.,2008). Evidently, multiple ciliary signalingpathways, involving Wnt, Hh and RTKsignaling take part in the regulation ofadipogenic differentiation.

PerspectiveBecause of its near-ubiquity on cells of thehuman body, and because of the multiplesignaling pathways that require it both duringdevelopment and in the adult, the primary ciliumhas moved from being nearly forgotten to aposition of considerable importance inbiomedicine. This is amply demonstrated forprimary cilia in the kidney and there areimportant data that indicate how signalingpathways involving the cilium might affectother tissues.

One persistent unanswered question aboutciliary function is why certain receptors andchannels are concentrated more or lessexclusively in the membrane of the primarycilium. Clearly, signaling molecules or secondmessengers that leave the cilium are initiallyspatially localized at the basal body orcentrosome, which would not be true of signalsarising from receptors or channels at the leadingedge of the cell or dispersed in the cellmembrane. Signals from the cilium mighttherefore interact with, activate or inactivatespecific centrosomal proteins to controltrafficking to the Golgi, to the leading edgeof a migrating cell, to cell junctions or, in thecase of transcription factors, to the nucleus.Ciliary orientation might impose a gradientof second messengers or effector moleculeswithin the cytoplasm to help determinepositioning of organelles and the mitoticspindle.

In certain cases, the amplitude of the signal orthe concentration of signaling molecules arisingfrom the cilium might be compared at thecentrosome to signals arising from elsewhere in

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the cell to determine a specific physiologicaloutcome, such as entry into the cell cycle andresorption of the cilium. At present, there areonly hints of how this computation might beperformed. As we learn more about IFT-complex assembly and IFT cargo, the role ofactivation of vesicular trafficking andexocytosis in building the cilium, and targetingprocesses in the cell in general, we might cometo understand reasons for sequestration withinthe primary cilium more completely. In turn, wemight be able to understand why differentreceptors are sequestered in different cilia, whythere are ‘yin-yang’ pairs of ciliary receptors andwhy sequestration of ciliary receptors andeffectors is so dynamic.

We apologize to those authors whose work has not beencited because of space limitations. P.S. is partiallyfunded by the NIH (NIDDK). S.T.C. and L.B.P. arepartially funded by grants from the LundbeckFoundation (R9-A969), the Novo Nordisk Foundation,and the Danish Natural Science Research Council (272-070530). We thank Bradley K. Yoder for valuablecomments on the manuscript and the poster. Depositedin PMC for release after 12 months.

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