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if cilia provide information that serves to retain cells in their functioning differentiated g0 state , then defects in this pathway are predicted to cause proliferative disorders : cancer , cystic diseases , and fibroses of various sorts . to date , the best case for such a role for cilia comes from studies on the polycystic kidney diseases ( pkds ) .
a growing body of evidence indicates that dysfunctional ciliary signaling is the proximal cause of cyst development .
consequently , mutant genes that trigger development of the pathology are candidates for players in the normal pathways of communication between cilia and the cell cycle regulatory machinery .
renal cysts are a devastating feature of a wide range of diseases , many of which have multi - organ pathology .
monoclonal cysts form from epithelial cells in the nephron , which proliferate and detach from their neighbors , eventually leading to end stage renal disease ( wilson , 2004 ) .
the idea that defective cilia are the proximal cause for pkd originated with the discovery that the causative gene of the mouse orpk pkd model , polaris , is homologous to a gene essential for ciliary assembly in chlamydomonas , ift88 ( pazour et al . , 2000 ) .
many proteins associated with pkd and related diseases or syndromes have since been shown to localize to cilia and basal bodies , and/or shown to play roles in ciliogenesis ( badano et al .
a direct causal connection between cilia and proliferation has been controversial because many of the implicated proteins are not exclusively ciliary . however , the idea that dysfunctional ciliary signaling is the proximal cause of aberrant cell proliferation in the kidney is strengthened by several recent lines of evidence .
the polycystins pc-1 and pc-2 ( products of pkd1 and pkd2 ) are subunits of a mechano - sensitive calcium channel that has been implicated as a flow sensor for the epithelial cells of kidney tubules ( boletta and germino , 2003 ) .
postulated mechanisms by which pc-1/pc-2 might retain the differentiated epithelial cells in g0/g1 include activation of the cyclin kinase inhibitor p21(waf1 ) via jak - stat ( bhunia et al . , 2002 ) and
blockade of camp - stimulated cell proliferation via atk - mediated inhibition of b - raf ( yamaguchi et al . , 2004 ) .
calcium - induced changes in proliferative state require sustained ca changes in order to affect gene transcription ; current data implicates both the calcineurin  nfat pathway ( puri et al . , 2004 ) and ap-1 ( bhunia et al . , 2002 ;
it is intriguing to note that pc-1 may mediate some of its effects by regulated cleavage and nuclear translocation ( chauvet et al . , 2004 ) .
it will be interesting to learn whether the cleaved product of pc-1 travels to the nucleus with kap : in the sea urchin , the kap component of the kinesin-2 motor necessary for anterograde ift moves into the nucleus as cilia resorb before mitosis ( morris et al . , 2004 ) .
nuclear kap may serve as a signal to the cell that the cilia have indeed been resorbed and cell division may now proceed . another cystogenic protein , inversin , which localizes to centrioles and cilia , binds both calmodulin and apc2 of the anaphase - promoting complex ( morgan et al .
, 2002a , b ) , thus providing another potential link between the sensory function of the primary cilium and the regulation of the cell cycle . beyond the kidney , other pathways important for cell growth or differentiation have been found to involve cilia ( pazour and witman , 2003 ) ; for example , in neuronal cells , somatostatin receptor 3 is targeted to primary cilia ( handel et al . , 1999 ) .
mouse knockouts of ift genes essential for ciliary assembly are embryonic lethal , with phenotypes reminiscent of mutations in the hedgehog pathway , suggesting that the hedgehog receptors localize to cilia ( huangfu et al . , 2003 ) .
in nih 3t3 cells , the tyrosine kinase receptor pdgfr , activation of which is sufficient for a quiescent cell to reenter the cell cycle , is expressed specifically on the primary cilium ( christensen et al . , 2004 ) .
surprisingly , bovine insulin promotes the growth of low - density cultures of the ciliate tetrahymena ( christensen , 1993 ) .
the insulin signal may be received by an insulin receptor - related tyrosine kinase which localizes to the tetrahymena cilia ( christensen et al . , 2003 ) .
antennae  for growth signals may be , like cilia themselves , a primitive condition of the eukaryotes .
all cells lose their cilia by one of two mechanisms : resorption or deflagellation / deciliation .
resorption is the process by which the cilium is gradually retracted into the cell , and usually occurs in advance of cell division .
deflagellation is the shedding of flagella that occurs in response to a wide range of stimuli .
it involves the precise severing of the nine outer doublet microtubules at the base of the flagellum , but distal to the transition zone between the basal body and the flagellum - proper , at a site known as the site of flagellar autotomy ( sofa ; mahjoub et al . , 2004 ) .
deflagellation is a common cellular response : sea urchin embryos , scallop gills , rabbit oviduct , porcine respiratory tissue , and rat cerebral ependymal cells all deciliate in response to stress ; cells regenerate their cilia when the stressful stimulus is removed ( quarmby , 2004 ) .
the fa2 gene was uncovered in a genetic screen for chlamydomonas mutants defective in deflagellation ( finst et al . , 1998 ) .
fa2p is essential for calcium - activated axonemal microtubule severing during deflagellation , and , as it turns out , it also plays a role during cell cycle progression ( mahjoub et al . , 2002 ) .
fa2p is a member of the nima - related kinase family , which is represented by at least eleven genes in humans ( the nima - related expressed kinases ; neks ) .
nek family members are known as cell cycle kinases ( o'connell et al . , 2003 ) , thus the discovery of a nek having a ciliary function was provocative .
fa2p localizes specifically to the sofa region of the cilium of interphase cells ( fig .
although fa2p 's ciliary function is directly related to axonemal severing , localization of the protein shows interesting changes during premitotic flagellar resorption and during ciliogenesis . during resorption
, fa2p relocates from the sofa to the proximal end of the basal bodies ; during mitosis , it is associated with the polar region of the mitotic spindle .
as the cells exit mitosis , fa2p accumulates at the proximal end of the basal bodies and moves out to the sofa as soon as ciliogenesis is initiated ( mahjoub et al . , 2004 ) . when expressed in imcd-3 cells ( derived from murine kidney ) , gfp - tagged chlamydomonas fa2p shows an intriguing pattern of localization . in a confluent culture
, fa2p is observed lying on the presumptive ciliary sofa and at the base of both centrioles , one of which is serving as the basal body ( mahjoub et al . , 2004 ) .
during mitosis , fa2p is associated with the duplicated centrioles and then with the polar region of the mitotic spindle in the mouse cells , as it is in chlamydomonas .
perhaps a functional homologue of fa2p facilitates the timing of the final break between daughter cells via triggering severing of the acetylated microtubules .
( a ) fa2p - ha localizes to the sofa region of the proximal axoneme ( arrowheads ) and also associates with basal bodies .
indirect immunofluorescence images visualized by anti - ha ( red ) , anti-tubulin ( blue ) , and anti - centrin ( green ) .
we do not yet know how fa2p mediates its effects on microtubule severing during deflagellation , or on the g2/m transition .
one possibility for the delay in entry into mitosis is that it is a consequence of inefficient flagellar resorption , relating to the ciliary function of fa2p .
although deflagellation has been considered a distinct pathway from premitotic flagellar resorption , recent evidence indicates that these two mechanisms of flagellar loss share important signaling components ( parker and quarmby , 2003 ; pan et al . , 2004 ) .
it is also possible that fa2p independently affects deflagellation and progression through the cell cycle : a presumptive kinase - dead fa2p localizes correctly to the sofa , but does not rescue the deflagellation defect of fa2 cells ; this same mutant protein provides full rescue of the g2/m delay ( mahjoub et al . , 2004 ) .
cnk2p is another member of the chlamydomonas nek family , and it is the second nek protein shown to be axonemal ( fig . 1 b ; bradley and quarmby , 2005 ) .
although fa2p is specifically localized to the sofa , cnk2p is found along the entire length of the axoneme .
the roles of cnk2p in the cilia and in cell cycle regulation are also distinct from fa2p .
when wild - type chlamydomonas cells pass the commitment point of the cell cycle , two decisions are made : whether to divide and if so , how many times .
cells then undergo a rapid succession of alternating m / s phases , dividing one , two , or three times , depending on the size of the cell when it passed the commitment point ( pickett - heaps , 1975 ) .
cells with altered cnk2p expression are defective at assessing their size at the commitment point : an increase in the amount of cnk2p results in small cells , while a decrease in cnk2p results in large cells .
these same manipulations of cnk2p levels produce cells with short and long flagella , respectively .
flagellar length is normally tightly controlled , at least in part by a balance in the rates of assembly and disassembly ( marshall , 2004 ) .
our data indicate that cnk2p may play a role in flagellar disassembly ; whether this role is independent of cell size assessment is unknown . in tetrahymena
, at least four neks localize to cilia and affect ciliary length ( j. gaertig , personal communication ) .
the relationship between the disassembly that contributes to length control , premitotic flagellar resorption and the assessment of cell size are all important connections that remain to be established .
we speculate that the nek family provides an important general connection between cilia and the regulation of cell cycle progression . in all organisms where they have been studied , nima and its brethren , the neks ,
we have noted that this family is expanded in lineages with ciliated cells ( bradley et al . , 2004 ) , but the only direct ciliary connection so far in vertebrates comes via studies of pkd models : the causative genes of two mouse pkd models are neks .
study of kat mutant mice established that nek1 carries the causative mutation in this model of autosomal recessive pkd ( upadhya et al . , 2000 ) .
hnek1 has been found to bind to other cystogenic proteins including kinesin-2 , which is also required for ciliogenesis ( surpili et al . , 2003 ) .
nek8 carries the causative mutation in the juvenile cystic kidney mouse model , and morpholinos to zebrafish nek8 cause kidney cysts in that organism ( liu et al . ,
a kinase domain mutation of the human orthologue of nek8 affects cell cycle progression , probably at the g2/m checkpoint .
it is currently unknown whether nek1 , nek8 , or any other mammalian neks , localize to cilia , but the work in chlamydomonas suggests that mammalian neks will be found in cilia .
it is interesting to consider that if cilia are indeed sending signals that regulate cell cycle progression , by physical necessity these signals must pass near or through the centrosome , which is a gathering place for all manner of cell cycle  regulating proteins ( doxsey , 2001 ; badano et al . , 2005 ) .
we are intrigued by the possibility that signals from the cilium are mediated by calcium .
calcium is implicated in both exit from g0 and at g1/s ( means et al . , 1999 ) , as well as ciliary disassembly ( quarmby , 2004 ) .
it is clear that there is a relationship between cilia , cell size , and cell cycle progression .
the extent to which cilia send signals that regulate cell cycle progression ( and vice versa ) is not yet known , but we predict that this area of research will provide fertile ground for the discovery of new players in the regulation of cell proliferation and differentiation .
available data indicates that most vertebrate cells are ciliated and that the genesis and disassembly of these cilia is coordinated with progression through the cell cycle .
we are only beginning to understand how this coordination is achieved , but its significance may be profound .
a recent convergence of data indicating a relationship between cilia and proliferative diseases , such as polycystic kidney disease , has revived the long - standing enigma of the reciprocal regulatory relationship between cilia and the cell cycle . 
 multiple signaling pathways are localized to cilia in mammalian cells , and some proteins have been shown to act both in the cilium and in cell cycle regulation . work from the unicellular alga chlamydomonas is providing novel insights as to how cilia and the cell cycle are coordinately regulated .