although in 1835 , purkinje and valentin ( 1835 ) published the first treatise to include studies of mammalian cilia , the history of what may be considered modern research on mammalian cilia does not extend back more than a few years longer than the history of this journal .
motile mammalian cilia attracted the attention of microscopists before the advent of electron microscopy , because they moved and were obviously similar in this motion to protozoan cilia . nevertheless , several light microscope structures whose later fine structure appearance ( and molecular biology ) had little in common with cilia were nevertheless labeled cilia , including the stereocilia of the hair cells , which are in fact modified microvilli . in 1954 ,
the electron microscope observations of fawcett and porter ( 1954 ) definitively characterized the 9  +  2 pattern of the cytoskeleton , the axoneme , of motile mammalian and other cilia .
they showed that this structure was enclosed by an extension of the cell membrane , the ciliary membrane .
the axoneme of true cilia was always an extension of a basal body and related to the nine - fold construction of the centriole . by 1956 , porter ( 1957 ) and de robertis ( 1956 ) realized that cilia were found as sensory structures in , for example mammalian photoreceptors , where the central pair of microtubules in the axoneme was absent , and the cilia were nonmotile , hence 9  +  0 .
finally , in the early 1960s , a number of electron microscopy studies showed that solitary 9  +  0 cilia , now termed primary cilia , are present on many differentiated cells of tissues of the mammalian and vertebrate body , including kidney cells , fibroblasts , neurons and even schwann cells ( barnes 1961 ; sorokin 1962 ; grillo and palay 1963 ) .
although specific antibodies against detyrosinated and acetylated tubulin became available to detect primary cilia in immunofluorescence microscopy ( piperno et al .
1987 ; cambray - deakin and burgoyne 1987 ) , primary cilia were generally neglected as interesting cell organelles .
the biggest problem was that primary cilia had no demonstrable function , even though considerable circumstantial evidence suggested that they were some form of chemical or mechanical sensor . on this basis ,
poole et al . ( 1985 ) proposed that primary cilia of connective tissue cells functioned as a cellular cybernetic probe , or in current terminology , as a cellular global positioning system .
roth et al . ( 1988 ) then demonstrated that primary cilia on cultured kidney epithelial cells could be bent by flow , and wheatley ( 1995 ) suggested that if primary cilia in renal epithelia did not function properly in sensing flow , there would be pathophysiological consequences .
while early studies of mammalian cilia focused on showing that the mechanism and biochemistry of motility was virtually identical to that discovered in other cilia , more recent studies have examined the way that cilia are built .
these studies have led to novel insights for both motile and nonmotile , including primary , cilia .
all cilia can now be viewed as sensory cellular antennae that coordinate a plethora of cellular signaling pathways , and this view has had unanticipated consequences for our understanding of developmental processes and disease . a recent review of mammalian cilia structure and function covering many of the topics presented here , in further detail , is found in satir and christensen ( 2007 ) .
the basic mechanism of ciliary motility is now reasonably well understood , although many details of how waveform is generated and propagated remain obscure . while much of the information about this mechanism was derived from protistan and invertebrate organisms ( satir 1985 )
, the basic principles clearly apply to mammalian cilia of the respiratory and reproductive tract , and to brain ependymal cilia .
cross - sections show the 9  +  2 axoneme of motile cilia ( asterisk ) .
the axoneme grows from a basal body , with a basal foot ( arrowhead ) pointing in the direction of the effective stroke .
the transition zone between basal body and axoneme contains the ciliary necklace ( arrow ) .
( from dirksen and satir 1972 , unpublished , with permission ) classic transmission electron micrograph of mouse oviduct cilia .
cross - sections show the 9  +  2 axoneme of motile cilia ( asterisk ) .
the axoneme grows from a basal body , with a basal foot ( arrowhead ) pointing in the direction of the effective stroke .
the transition zone between basal body and axoneme contains the ciliary necklace ( arrow ) .
( from dirksen and satir 1972 , unpublished , with permission ) ciliary motility is caused by the relative sliding of the nine outer axonemal doublets , operating as two opposing sets , one ( doublets 14 ) to produce the effective stroke ( or principal bend in flagella ) , one ( doublets 69 ) to produce the recovery stroke ( or reverse bend ) , powered by atp and a set of molecular motors , the axonemal dyneins .
the axonemal dyneins are arranged in two sets of arms : the outer dynein arms ( odas ) consisting of two heavy - chain dynein isoforms in mammalian cilia , packaged with intermediate and light chains , with four identical odas , each aligned along 96-nm long doublet microtubule ( nicastro et al .
the idas , more centrally located , consist of at least seven heterodimeric and monomeric heavy - chain dynein isoforms per 96  nm .
generally , the odas and idas function together , but the odas principally regulate beat frequency , in part by camp - dependent phosphorylation of an oda regulatory light chain , while the idas control beat form . both frequency and form change by changing the rate of sliding and the switching of activity between the doublet sets . sliding is converted into propagated bending , most efficiently by control of ida activity via phosphorylation and mechanical interaction involving the radial spoke , central pair complex . in effect , the 9  +  2 axoneme is a nanomachine composed of perhaps over 600 proteins in molecular complexes , many of which also function independently as nanomachines . the enzymes that control axonemal response , for example protein kinase a , are structurally part of the complexes .
strong support for this mechanism of ciliary motility comes from studies of paralyzed and other mutants of protistan cilia , where a structural defect and a corresponding genetic mutation can directly be correlated with a change in ciliary beat .
similarly , strong support for the applicability of the mechanism to human cilia comes from studies , mainly of ciliary structural defects and genetic mutations associated with impaired mucociliary function in the respiratory system , which produces sinusitis and bronchiectasis .
clinical features of pcd , which include chronic rhinitis / sinusitis , otitis media , male infertility and an increased incidence of hydrocephalus , point to physiological processes where ciliary motility is essential ( afzelius 2004 ) . as might be anticipated , prominent causes of pcd are mutations that affect the assembly or function of the dynein arms  most commonly a mutation in dnah5 , a gene encoding a dynein heavy chain of the odas ( olbrich et al .
any mutation affecting the ciliary beat mechanism will potentially produce pcd , depending on the severity of beat impairment .
an instructive example is hydin , a component of the central pair projection complex that interacts with the radial spokes in the switching mechanism between doublet sets .
hydin - deficient flagella of chlamydomonas become intermittently paralyzed , stopping for long times at the end of the effective or recovery strokes , where the direction of beat is reversed ( lechtreck and witman 2007 ) .
mutant cilia were unable to bend properly and frequently stalled , implying that because central pair structure was defective , interactions between the central pair and the radial spokes that affected dynein arm switching were abnormal , and consequently cilia - generated flow was impaired .
one would predict that human mutations in hydin are also likely to result in hydrocephalus or a form of pcd .
many people diagnosed with pcd have situs inversus totalis that is reversal of left  right asymmetry of body organs such as the heart .
this is now known to be produced , because fluid flow produced by motile cilia at the embryonic node is defective ( hirokawa et al .
the usual flow pattern produced by the cilia is unidirectional right - to - left , and this activates a left - side - only gene cascade , probably by impinging on primary cilia at the left side of the node ( mcgrath et al .
the nodal cilia are mainly missing the central pair of axonemal microtubules , hence , although motile , are often 9  +  0 , but with some unique oda dynein isoforms ( supp et al . 1999 ) .
it is not known whether the response of the primary cilia at the node is to mechanical displacement ( flow sensing ) or if it involves morphogens produced in membrane parcels in the node ( tanaka et al . 2005 ) .
morphogen - containing multimembrane vesicles are a feature of nodal response that could also apply respiratory and other ciliated epithelia , where flow occurs .
while mouse mutants or knockouts that are missing cilia develop situs inversus , hydin mutants do not show this phenotype , presumably because their motility is sufficient to generate appropriate nodal flow . in a similar way , by examining the pcd phenotype of mutations in various ciliary proteins , identified by proteomics , it should be possible to dissect details of the function of the protein in the mechanism of beat generation ( avidor - reiss et al . 2004 ; badano et al .
a major breakthrough in the understanding of the importance of cilia in the body has come from the study of chlamydomonas ciliogenesis .
ciliogenesis involves transport of materials into , along and out of the cilium , directly visualized as 
ift requires molecular motors , several kinesins for anterograde transport and a specialized cytoplasmic dynein for retrograde transport . coupling the transported cargo to the molecular motors that move along the outer doublets of the axoneme
remarkably , this machinery is conserved almost universally wherever cilia are built , and orthologs of the motors and ift proteins are found in sensory cilia and their derivatives , such as the mammalian photoreceptor ( baker et al .
however , motile cilia of mammalian tissues often assemble in mass ( gaillard et al . 1989 ; dirksen 1991 ) .
centriologenesis of hundreds of basal bodies occurs from a fibrogranular mass in the cytoplasm and cilia sprout from the cell surface .
it is unclear whether classical ift is the major mechanism of ciliogenesis in respiratory epithelium , or what modifications of the process occur .
( 1971 ) and archer and wheatley ( 1971 ) studied ciliogenesis of primary cilia of established cell lines in vitro .
postmitotic cells reassemble primary cilia in g1 and maintain the cilium as the cells enter growth arrest ( g0 ) and undergo differentiation .
in contrast to motile cilia , the primary cilium emanates uniquely from the distal end of the existing mother centriole of the centrosome , which migrates to the cell surface during growth arrest .
ciliogenesis by ift is initiated while the centrosome is positioned at the golgi apparatus near the nucleus , while extensive ift and elongation of the cilium take place after docking of the nascent cilium at the cell surface , where microtubule pairs are quickly assembled to form the mature axoneme .
two recent and extensive reviews of the complex interactions between ift particles , molecular motors , centrosomal proteins and other microtubule - associated proteins in ciliogenesis are presented in pedersen et al .
the first human illness that could be linked to primary cilia in epithelial cells was polycystic kidney disease ( pkd ) .
one of the orthologs of ift88 is the mammalian protein polaris mutated in a transgenic mouse tg737 , which was a model for the study of pkd .
( 2000 ) demonstrated that , similarly , cilia of the mouse kidney were abnormally short or missing , which suggested that pkd might be a ciliary disease .
mechanical deflection of kidney tubule epithelial cells induces an increase in intracellular calcium ( praetorius and spring 2001 ) , and the pkd proteins , polycystins 1 and 2 in ca - signaling , localize to the ciliary membrane ( pazour et al .
many other proteins whose functions are disrupted in cystic diseases , e.g. nephrocystins , have now been localized to the cilium or at the ciliary basal body , supporting the conclusion that the primary cilium in kidney tubules partly functions as a mechanosensor that , upon bending , activates a series of signaling pathways in the cilium to control development and homeostasis of the tissue ( for reviews , see yoder et al . 2007 ; hildebrandt and zhou 2007 ) , as originally envisaged by roth et al .
thus , even if primary cilia are present , unless these proteins are targeted appropriately to the cilia or the ciliary basal body , pathology develops .
it is now clear that the ciliary membrane is a privileged and specialized compartment for receptor signaling and that the polycystins are only one type of many membrane proteins that must be targeted to the primary cilium to function properly .
further , essential downstream components in pdgfr and hedgehog signaling as well as signaling in neurotransmission , wnt pathways , extracellular matrix interaction and osmolyte transportation uniquely localize to the cilium and/or to the ciliary centrosome ( gerdes et al . 2007 ; corbit et al . 2008 ; for reviews , see singla and reiter 2006 ; michaud and yoder 2006 ; christensen et al . 2007 ; christensen and ott 2007 ) . in many of these signaling systems ,
deficiencies in placement of receptors and their immediate downstream signaling components in the cilium or at the ciliary base results in ciliopathy , including cystic kidney , pancreatic and liver diseases , retinitis pigmentosa , cancer , defective neurogenesis , bardet - biedl syndrome , polydactyly , anosmia and other developmental defects . in the tg737 mouse ,
2 , primary cilia with hedgehog receptor pathway signaling are found on human embryonic stem cells ( kiprilov et al . 2008 ) , which suggests that ciliary signaling is involved in differentiation from the beginning of embryogenesis . in embryogenesis , signaling through the primary cilium is necessary for normal development , probably because such signaling regulates the balance between cell division , polarity , migration , differentiation and apoptosis for many tissues . 

immunofluoresence microscopy using acetylated  tubulin antibody ( tb ) reveals the presence of primary cilia ( arrows ) on human embryonic stem cells . in the absence of stimulation ,
the hedgehog receptor  patched ( ptc ) colocalizes with the acetylated  tubulin all along the ciliary membrane .
nuclei are stained with dapi ( blue ) . upon stimulation , as part of the signaling cascade , ptc leaves the cilium and the smoothened receptor ( smo ) enters to activate the hedgehog signaling cascade .
( from kiprilov et al . 2008 , with permission , courtesy of the journal of cell biology ) primary cilia of human embryonic stem cells .
immunofluoresence microscopy using acetylated  tubulin antibody ( tb ) reveals the presence of primary cilia ( arrows ) on human embryonic stem cells . in the absence of stimulation ,
the hedgehog receptor  patched ( ptc ) colocalizes with the acetylated  tubulin all along the ciliary membrane .
nuclei are stained with dapi ( blue ) . upon stimulation , as part of the signaling cascade , ptc leaves the cilium and the smoothened receptor ( smo ) enters to activate the hedgehog signaling cascade .
primary cilia persist in many differentiated cells , including kidney tubule epithelial cells , fibroblasts and neurons , after organogenesis is complete and cell division rates fall . presumably , as semipermanent structures , the cilia function as mechano- or chemosensors and as a cellular global positioning system to detect changes in the surrounding environment , to initiate cellular replacement after damage , for example . to test this hypothesis ,
techniques are being used to knock out primary cilia or ciliary proteins in specific tissues of adult organisms .
( 2007 ) have completed one of the first of these studies , using an inducible system in adult mice to disrupt ift in several different ways , causing loss of primary cilia .
surprisingly , when primary cilia are lost from all adult tissues , the devastating abnormalities and lethality seen after embryonic loss of cilia are not observed .
this delay correlates well with a greatly reduced rate of cell division and a different pattern of gene expression in the mature kidney and could explain the increase in human pkd with age .
such changes in cell proliferation rate may relegate the primary cilium of adult tissues to a less immediate role , involving long - term homeostasis of the tissue . because signaling through primary cilia is coupled to cell cycle events , for example in pdgfr signaling in fibroblasts , long - term disruption of ciliary signaling could be a factor in oncogenesis .
one adult tissue responds immediately to ciliary knockout however  that is nervous tissue , most specifically neurons in the hypothalamus .
knockout of all adult primary cilia in the mouse , or specifically only of primary cilia on pomc neurons , leads to hyperphagia  compulsive and excessive eating  leading to obesity .
these defects do not occur if the knockout mice are kept on a restricted diet . eating behavior
these fndings suggest that the leptin receptor might be located in the membrane of the primary cilia of the pomc neurons .
the hypothalamic hormone somatostatin is a negative regulator of leptin . while leptin leads to reduced eating , somatostatin increases eating behavior .
the somatostatin receptor sst 3 is localized to primary cilia in hypothalamic neurons ( stepanyan et al . 2007 ) .
( 2007 ) suggest that , much like the patched and smoothened receptors work in hedgehog signaling , the leptin receptor and a somatostatin receptor could work in a yin - yang relationship within the pomc primary cilium ( satir 2007 ) .
whatever the precise cell biological explanation of the relationship between ciliary knockout and hyperphagia , the effect of knockout is behavioral .
we might expect that mutations in other proteins of neuronal primary cilia could lead to other behavioral responses .
there are reports that the rages that fueled the famous hatfield - mccoy feud of appalachia probably were driven by a family suffering from von hippel - landau ( vhl ) syndrome .
perhaps a more ciliocentric view of neuronal activity affecting recurrent or addictive actions is warranted .
beginning with important electron microscopic studies and culminating in immunolocalization combined with molecular genetic technology , much has been learned about motile , sensory and primary cilia in mammals .
defects in building the primary cilium or mutations in ciliary membrane or axonemal proteins lead to ciliopathies , important human diseases .
the cilium has moved to a prominent place in studies of embryogenesis and tissue differentiation and maintenance .
there are hints that the fundamental cell biology of cilia will also be important in oncogenesis , aging diseases and human behavioral disorders .
the strides of the past half century in understanding this organelle have been impressive , and the promise of discovery in the next half century is compelling .
 in the past half century , beginning with electron microscopic studies of 9  +  2 motile and 9  +  0 primary cilia , novel insights have been obtained regarding the structure and function of mammalian cilia . 
 all cilia can now be viewed as sensory cellular antennae that coordinate a large number of cellular signaling pathways , sometimes coupling the signaling to ciliary motility or alternatively to cell division and differentiation . 
 this view has had unanticipated consequences for our understanding of developmental processes and human disease . 
Introduction
The mechanism of ciliary motility and primary ciliary dyskinesia
Principles of ciliogenesis
Ciliopathies
Primary cilia in adult tissues
Conclusions