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PubMed2006

Cilia: tuning in to the cell's antenna.

Cilia are microtubule-based organelles that project like antennae from the surface of most cells in the body. Motile cilia move fluid past cells, for example mucus in the airway. Non-motile primary cilia, however, transduce a multitude of sensory stimuli, including chemical concentrations of growth factors, hormones, odorants, and developmental morphogens, as well as osmolarity, light intensity, and fluid flow. Cilia have evolved a complex ultrastructure to accommodate these diverse functions, and an extensive molecular machinery has developed to support the assembly of these organelles. Defects in the cilia themselves, or the machinery required to assemble them, lead to a broad spectrum of human disease symptoms, including polycystic kidney disease, nephronophthisis, hydrocephalus, polydactyly, situs inversus, retinal degeneration, and obesity. While these diseases highlight the pivotal roles of cilia in physiology and development, the mechanistic link between cilia, physiology, and disease remains unclear.

Animals↗

PubMed2000

Length control of primary cilia: analysis of monociliate and multiciliate PtK1 cells.

Lengths of primary cilia in cultured PtK1 cells, on both a population basis and within individual (multiciliate) cells, have been compared. The latter examines the degree of discrepancy between cilia arising within the same cell and using a common precursor pool, on the hypothesis that a better correlation would be expected between cilia issuing from the same centrosome than between those in the population in general. To obtain accurate et plentiful measurements, a 'flow-fixation' technique was devised, which flattens the long primary cilia of cultured PtK1 cells (a kidney epithelial cell line from Potorous tridactylus, the kangaroo rat), prior to immunostaining with an antibody directed against detyrosinated tubulin (ID5). Comparisons of the flow-fixed measurements with a through-focus procedure for upright cilia in conventionally fixed cultures showed reasonable agreement, but not as closely as with measurements made on the living cells using the edge-on method of Roth et al. (J. Cell Sci. 89 (1988) 457). The incidence of multiciliation of confluent PtK1 cells cultures was approximately 5%, of which the majority were biciliates. Although shaft length in general varied considerably, biciliates and multiciliates showed a greater internal consistency, with discrepancies of < 25% in 70% of the cases. On both accounts, this consistency is far poorer than in, for comparison, Chlamydomonas, where its two flagella were < 5% different in length and within 10% tolerance throughout the whole population. Thus, length of primary cilia in PtK1 cell populations is considerably less stringently controlled than in PtK1 cells bearing 9 + 2 cilia, but those issuing from a single multiciliated cell tend to show better correspondence.

Animals↗

PubMed1998

Localization of a G protein Gi2 in the cilia of rat ependyma, oviduct and trachea.

In previous studies, the localization of a pertussis toxin-sensitive G protein was demonstrated in ependymal cilia, but the identification of the subtype of G protein was inconsistent. To clarify this issue, we studied the localization of Goalpha, Gi1alpha, Gi3alpha and Gi2alpha in the ciliated ependymal cells and in the cilia of some other tissues of rats using specific antibodies. The cilia of the ependymal cells that line the ventricular cavity of the brain were intensely immunoreactive for Gi2alpha, but not for Goalpha, Gi1alpha or Gi3alpha. Immunoblot analysis demonstrated higher levels of Gi2alpha in the ependymal cilia-rich pellet than in the motor area of the parietal cortex. At the ultrastructural level, the immunoreactivity specific for Gi2alpha was found predominantly in the cilia, but rarely in the microvilli or the basal bodies of ependymal cells. In cross-sections, the immunoreactivity specific for Gi2alpha was observed only in cell membranes, in particular, in the inner electron-dense leaflet of the trilaminar structure. In addition to that in the ependymal cilia, such specific localization of Gi2alpha was observed in the motile cilia in other tissues, including the oviduct and trachea. By contrast, the stereocilia in the ductus deferens were not immunopositive for Gi2alpha. These findings suggest that Gi2 might play an important role in the signal transduction in ciliary membrane-associated function(s) of the ependymal cells, oviduct and trachea.

Animals↗

PubMed2006

Primary cilia deletion in pancreatic epithelial cells results in cyst formation and pancreatitis.

BACKGROUND & AIMS: Defects in cilia formation or function have been implicated in several human genetic diseases, including polycystic kidney disease (PKD), Bardet-Biedl syndrome, and primary ciliary dyskinesia. Pancreatic lesions are found in approximately 10% of PKD patients, suggesting a connection between cilia defects and pancreatic pathologies. Here, we investigate the role of cilia in pancreas formation and function by analyzing mice that lack cilia in pancreatic cells. METHODS: Using Cre/lox technology, we conditionally inactivated Kif3a, the gene encoding for a subunit of the kinesin-2 complex that is essential for cilia formation, in pancreatic epithelia. Kif3a mice were studied by immunohistochemical and biochemical methods to assess the morphology and differentiation status of pancreatic cells. RESULTS: Tissue-specific loss of Kif3a in pancreatic cells resulted in severe pancreatic abnormalities including acinar-to-ductal metaplasia, fibrosis, and lipomatosis. Ductal metaplasia appears to be due to expansion of ductal cells rather than transdifferentiation of acinar cells. Cyst formation, aberrant ductal morphology, and extensive fibrosis associated with severe adhesion to adjacent organs were commonly observed in aged Kif3a mutant mice. Deletion of Kif3a using different pancreas-specific Cre strains suggests that these pancreatic phenotypes might be caused by the absence of cilia in ductal cells. Activation of transforming growth factor beta and Mitogen-activated protein kinase kinase/extracellular signal-regulated kinase (MEK/ERK) pathways may play a role in these phenotypes. CONCLUSIONS: These results demonstrate that the absence of cilia in pancreatic cells produces pancreatic lesions that resemble those found in patients with chronic pancreatitis or cystic fibrosis.

Animals↗

PubMed1997

Cilia internal mechanism and metachronal coordination as the result of hydrodynamical coupling.

We present a simple but realistic model for the internal bend-generating mechanism of cilia, using parameters obtained from the analysis of data of the beat of a single cilium, and incorporate it into a recently developed dynamical model. Comparing the results to experimental data for two-dimensional beats, we demonstrate that the model captures the essential features of the motion, including many properties that are not built in explicitly. The beat pattern and frequency change in response to increased viscosity and the presence of neighboring cilia in a realistic fashion. Using the model, we are able to investigate multicilia configurations such as rows of cilia and two-dimensional arrays of cilia. When two adjacent model cilia start beating at different phase, they synchronize within two cycles, as observed in experiments in which two flagella beating out of phase are brought close together. Examination of various multicilia configurations shows that metachronal patterns (i. e., beats with a constant phase difference between neighboring cilia) evolve autonomously. This provides modeling evidence in support of the conjecture that metachronism may occur as a self-organized phenomenon due to hydrodynamical interactions between the cilia.

Cilia↗

PubMed2002

Identification of dynein heavy chain 7 as an inner arm component of human cilia that is synthesized but not assembled in a case of primary ciliary dyskinesia.

Although the basic structure of the axoneme has been highly conserved throughout evolution, the varied functions of specialized axonemes require differences in structure and regulation. Cilia lining the respiratory tract propel mucus along airway surfaces, providing a critical function to the defense mechanisms of the pulmonary system, yet little is known of their molecular structure. We have identified and cloned a dynein heavy chain that is a component of the inner dynein arm. Bronchial epithelial cells were obtained from normal donors and from a patient with primary ciliary dyskinesia (PCD) whose cilia demonstrated an absence of inner dynein arms by electron microscopy. Cilia from normal and PCD cells were compared by gel electrophoresis, and mass spectrometry was used to identify DNAH7 as a protein absent in PCD cilia. The full-length DNAH7 cDNA was cloned and shares 68% similarity with an inner arm dynein heavy chain from Drosophila. DNAH7 was induced during ciliated cell differentiation, and immunohistochemistry demonstrated the presence of DNAH7 in normal cilia. In cilia from PCD cells, DNAH7 was undetectable, whereas intracellular DNAH7 was clearly present. These studies identify DNAH7 as an inner arm component of human cilia that is synthesized but not assembled in a case of PCD.

Amino Acid Sequence↗

PubMed1999

Role of a class DHC1b dynein in retrograde transport of IFT motors and IFT raft particles along cilia, but not dendrites, in chemosensory neurons of living Caenorhabditis elegans.

The heterotrimeric motor protein, kinesin-II, and its presumptive cargo, can be observed moving anterogradely at 0.7 microm/s by intraflagellar transport (IFT) within sensory cilia of chemosensory neurons of living Caenorhabditis elegans, using a fluorescence microscope-based transport assay (Orozco, J.T., K.P. Wedaman, D. Signor, H. Brown, L. Rose, and J.M. Scholey. 1999. Nature. 398:674). Here, we report that kinesin-II, and two of its presumptive cargo molecules, OSM-1 and OSM-6, all move at approximately 1.1 microm/s in the retrograde direction along cilia and dendrites, which is consistent with the hypothesis that these proteins are retrieved from the distal endings of the cilia by a retrograde transport pathway that moves them along cilia and then dendrites, back to the neuronal cell body. To test the hypothesis that the minus end-directed microtubule motor protein, cytoplasmic dynein, drives this retrograde transport pathway, we visualized movement of kinesin-II and its cargo along dendrites and cilia in a che-3 cytoplasmic dynein mutant background, and observed an inhibition of retrograde transport in cilia but not in dendrites. In contrast, anterograde IFT proceeds normally in che-3 mutants. Thus, we propose that the class DHC1b cytoplasmic dynein, CHE-3, is specifically responsible for the retrograde transport of the anterograde motor, kinesin-II, and its cargo within sensory cilia, but not within dendrites.

Animals↗

PubMed2004

Pericentrin forms a complex with intraflagellar transport proteins and polycystin-2 and is required for primary cilia assembly.

Primary cilia are nonmotile microtubule structures that assemble from basal bodies by a process called intraflagellar transport (IFT) and are associated with several human diseases. Here, we show that the centrosome protein pericentrin (Pcnt) colocalizes with IFT proteins to the base of primary and motile cilia. Immunogold electron microscopy demonstrates that Pcnt is on or near basal bodies at the base of cilia. Pcnt depletion by RNA interference disrupts basal body localization of IFT proteins and the cation channel polycystin-2 (PC2), and inhibits primary cilia assembly in human epithelial cells. Conversely, silencing of IFT20 mislocalizes Pcnt from basal bodies and inhibits primary cilia assembly. Pcnt is found in spermatocyte IFT fractions, and IFT proteins are found in isolated centrosome fractions. Pcnt antibodies coimmunoprecipitate IFT proteins and PC2 from several cell lines and tissues. We conclude that Pcnt, IFTs, and PC2 form a complex in vertebrate cells that is required for assembly of primary cilia and possibly motile cilia and flagella.

Animals↗

PubMed1974

The regeneration of cilia in partially deciliated Tetrahymena.

Partial deciliation of Tetrahymena resulted in cells losing 75% of their cilia, with the balance being paralyzed. The paralyzed cilia are resorbed in the first 20 min after partial deciliation, and regeneration of cilia begins before resorption is completed. Inhibition of protein synthesis with cycloheximide does not inhibit ciliary resorption or regeneration, whereas vinblastine sulfate inhibits regeneration but not resorption. Inhibition of regeneration occurs in completely deciliated cells when they are treated with cyclohexmimide or vinblastine sulfate. It is concluded that the resorbing cilia contribute materials which allow regeneration to occur in the absence of protein synthesis. The volume of cilia regenerated in the presence of cycloheximide in partially deciliated cells is greater than the ciliary volume which is resorbed. This suggests the Tetrahymena cells have a pool of ciliary precursors. This pool does not contribute materials for regeneration in completely deciliated cells which are treated with cycloheximide. It is concluded that resorbing cilia in partially deciliated cells contribute materials which potentiate assembly of cilia from the pool of precursors.

Amino Acids↗

PubMed1980

Ultrastructural features of respiratory cilia in cystic fibrosis.

The respiratory cilia of nine patients with cystic fibrosis were examined by electron microscopy. In contrast to patients with "immotile cilia syndrome," the cilia from the patients with cystic fibrosis contained dynein arms and radial spokes. A low percentage of abnormal cilia were detected in all nine patients, but, except for the occurrence of rippled cilia in these patients, the alterations were similar both in morphologic terms and incidence to alterations in a control group of patients with chronic bronchitis. Lesions included compound cilia, excess cytoplasmic matrix, and an abnormal number or arrangement of microtubular doublets. Patients suffering from cystic fibrosis do not exhibit ultrastructural ciliary alterations characteristic of immotile cilia syndrome.

Adolescent↗

PubMed2002

Comparison of mechanical agitation and calcium shock methods for preparation of a membrane fraction enriched in olfactory cilia.

Calcium plays an important regulatory role in olfactory signal transduction. Many investigations into the regulation of the olfactory signaling pathway have been performed using fractions enriched in ciliary membranes from olfactory sensory neurons. The traditional method of preparing ciliary fractions uses high calcium concentrations, thought to dislodge cilia from the dendritic knobs of the olfactory neurons in the nasal epithelium. However, calcium, an important second messenger in the odorant signaling cascade, modulates the activity of many enzymatic reactions in this cascade. Pre-exposure of cilia to high calcium concentrations may modify these signaling events. Therefore, we sought to develop a method of isolating cilia-enriched membranes that avoids exposing the cilia to high calcium concentrations. Our method of isolation, referred to as the mechanical agitation method, involves mechanical disruption and sonication of the olfactory epithelium to dislodge the cilia. To evaluate this method of cilia preparation, basal adenylyl cyclase activity, as well as forskolin- and odorant-activated adenylyl cyclase, were analyzed. Specific activity of adenylyl cyclase and protein yield were compared for the mechanical agitation and the high calcium preparations. Immunoblots were analyzed for the presence of transduction components enriched in olfactory cilia: adenylyl cyclase type III (ACIII), heterotrimeric G-protein subunit Galphaolf and the 1 C2 isoform of phosphodiesterase (PDE 1 C2). Based on these analyses, the ciliary fraction prepared by the mechanical agitation method appears to be very similar to that prepared by the high calcium method, with a higher yield.

Adenylyl Cyclases↗

PubMed1982

Genetic heterogeneity of dynein-deficiency in cilia from patients with respiratory disease.

Impairment of mucociliary clearance as a result of genetic defects of cilia in the respiratory tract has been recognized as a cause of chronic or recurrent respiratory diseases. Respiratory cilia have been examined by high resolution electron microscopy of nasal and bronchial biopsies from children and young adults from 6 months to 24 yr of age. In this series, 17 children with immotile cilia syndrome have been shown to have deficiencies of dynein arms in the cilia. Ultrastructural analysis reveals a variability of dynein defects from the lack of inner arms, the lack of outer arms, to the complete lack of both inner and outer dynein arms. The spectrum of defects that contribute to dynein-deficient cilia presumably reflects separate genetic determinants, affording further evidence that the immotile cilia syndrome is genetically heterogeneous. Despite ultrastructural differences in cilia, no significant differences are evident in the clinical course of the respiratory disease in affected subjects or in the incidence of situs inversus that affects 50% of subjects.

Adenosine Triphosphatases↗

PubMed1976

High speed cinemicrographic studies on rabbit tracheal (ciliated) epithelia: determination of the beat pattern of tracheal cilia.

High speed cinemicrographs reveal that the ciliary configuration and beat pattern of rabbit tracheal cilia differ significantly from classid descriptions, although the basic forward and return pattern is still observed. The tracheal cilia are short and stout (about 6 mum in length) and are of a slightly bent original configuration bent original configuration. At the start of the forward stroke, the cilia bear about 75-90 degrees to the epithelial surface in the direction of the forward stroke. The forward stroke is planar and consists of a simple "bowing" movement, without showing any progressive bending and without changing the original ciliary configuration. The complete forward stroke sweeps through an arc of about 35-40 degrees, with the tips of the cilia penetrating the bottom of the mucous layer through an arc of about 5-8 degrees at the start of each forward stroke. The return stroke starts from close to the epithelial surface and returns to the starting position of the forward stroke by reversing the planer forward pathway at a reduced speed. The stout nature of the cilia, the original bent ciliary configuration, the near vertical starting position of the forward stroke, the extent of the angular sweeps of the strokes, the peculiar "bowing" forward stroke movement, and the nature of the return stroke all serve to enhance efficiency in moving fluid forward. It has been documented that each forward stroke of the tracheal cilia caused and maintains a swift forward movement of the intermediate serous (liquid) layer of the mucociliary system. This movement, in turn, reacts hydrodynamically with the top mucous layer, and together with the clawing action of the tips of the cilia at the start of the forward stroke, causes the mucous layer to move cephalad in the manner of a conveyor belt.

Animals↗

PubMed2005

Dysfunctional cilia lead to altered ependyma and choroid plexus function, and result in the formation of hydrocephalus.

Cilia are complex organelles involved in sensory perception and fluid or cell movement. They are constructed through a highly conserved process called intraflagellar transport (IFT). Mutations in IFT genes, such as Tg737, result in severe developmental defects and disease. In the case of the Tg737orpk mutants, these pathological alterations include cystic kidney disease, biliary and pancreatic duct abnormalities, skeletal patterning defects, and hydrocephalus. Here, we explore the connection between cilia dysfunction and the development of hydrocephalus by using the Tg737orpk mutants. Our analysis indicates that cilia on cells of the brain ventricles of Tg737orpk mutant mice are severely malformed. On the ependymal cells, these defects lead to disorganized beating and impaired cerebrospinal fluid (CSF) movement. However, the loss of the cilia beat and CSF flow is not the initiating factor, as the pathology is present prior to the development of motile cilia on these cells and CSF flow is not impaired at early stages of the disease. Rather, our results suggest that loss of cilia leads to altered function of the choroid plexus epithelium, as evidenced by elevated intracellular cAMP levels and increased chloride concentration in the CSF. These data suggest that cilia function is necessary for regulating ion transport and CSF production, as well as for CSF flow through the ventricles.

Animals↗

PubMed1994

An electrophysiological survey of frog olfactory cilia.

Individual olfactory receptor neurons vary widely in their responses to odorants. Olfactory stimulus reception occurs in the cilia of the receptor neurons. Thus, the variability among individual neurons could in part be due to differences among the olfactory cilia. We have quantified the known conductance properties of each of 117 frog olfactory cilia. From a strictly qualitative viewpoint, the cilia were very homogeneous. All but a few of them had a basal conductance in the absence of odorants and second messengers, conductances stimulated by cytoplasmic cyclic AMP and by Ca2+ and a conductance measured in the presence of ATP and stimulated by GTP gamma S. However, the magnitudes of the conductances varied widely among the cilia. Amplitudes of the cyclic-AMP- and Ca(2+)-activated ciliary currents correlated strongly with one another across the 117 cilia and 24 frogs studied, suggesting that expression of the underlying channels may be co-regulated. None of the conductance properties correlated strongly with ciliary length, a marker of cell maturity. Given cytoplasmic MgATP as substrate, ciliary adenylate cyclase apparently produced cyclic AMP, which in turn gated membrane channels and increased the ciliary conductance. In some cilia, MgATP alone caused a very large increase in conductance. In others, there was little effect unless GTP gamma S, which increases cyclase activity, was also added. No effect of cytoplasmic inositol trisphosphate on ciliary conductance was detectable.

Adenosine Triphosphate↗

PubMed1979

Otitis media and the immotile cilia syndrome.

The immotile cilia syndrome appears to be a congenital defect in the ultrastructure of cilia that renders them incapable of movement. Respiratory tract cilia and sperm are predominantly affected. Bronchiectasis, sinusitis and male sterility are the main clinical findings. Situs inversus may be found. To these findings can be added otitis media. The defect appears to be a complete or partial absence of dynein arms which are believed to be essential for generating movement of cilia or sperm tails. Six patients suspected of having immotile cilia were compared to six patients in a control group. In affected patients, no cilia movement in the middle ear or nasopharynx was observed using the operating microscope. Electron microscopy of cilia from the mucosa of the middle ear and nasopharynx appeared to confirm the ultrastructural defect in two of six patients suspected of having the syndrome.

Adult↗

PubMed2006

Spontaneous creation of macroscopic flow and metachronal waves in an array of cilia.

Cells carrying cilia on their surface show many striking features: alignment of cilia in an array, two-phase asymmetric beating for each cilium, and existence of metachronal coordination with a constant phase difference between two adjacent cilia. We give simple theoretical arguments based on hydrodynamic coupling and an internal mechanism of the cilium derived from the behavior of a collection of molecular motors to account qualitatively for these cooperative features. Hydrodynamic interactions can lead to the alignment of an array of cilia. We study the effect of a transverse external flow and obtain a two-phase asymmetrical beating, faster along the flow and slower against the flow, proceeding around an average curved position. We show that an aligned array of cilia is able to spontaneously break the left-right symmetry and to create a global average flow. Metachronal coordination arises as a consequence of the internal mechanism of the cilia and their hydrodynamic couplings, with a wavelength comparable to that found in experiments. It allows the cilia to start beating at a lower adenosine-triphosphate threshold and at a higher frequency than for a single cilium. It also leads to a rather stationary flow, which might be its major advantage.

Biological Clocks↗

PubMed1997

Clinical relevance of tubulus anomalies and compound cilia.

Transmission electron microscopy (TEM) from nasal mucosa and nasal mucociliary transport rate (MTR) with a radio-isotopic method were examined in 144 patients with various respiratory symptoms. Examinations were not performed during acute infections. In cases of increased amount of tubulus anomalies: nasal MTR was not significantly slower than in other patients, the disorientation of ciliary beat direction was significantly larger, there was no connection with increased amount of compound cilia and there was no correlation to any specific symptom or respiratory disease. In cases of increased amount of compound cilia: nasal MTR did not differ from other patients and the disorientation of ciliary beat direction did not differ from other patients. In a follow-up study of 76 patients 5-11 years (mean 9.3 years) later the amount of tubulus anomalies and compound cilia had changed in most patients. In patients with less symptoms at the follow-up than primarily, there was a non-significant tendency to have less tubulus anomalies, too, but no change in the amount of compound cilia. The amount of tubulus anomalies and compound cilia is not stable. Their number can either increase or decrease during a follow-up. Tubulus anomalies are non-specific and probably secondary changes of minor clinical importance and compound cilia would seem to be quite irrelevant findings in the ultrastructural evaluation of respiratory cilia.

Adult↗