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PubMed1981

Kartagener's syndrome: a genetic defect affecting the function of cilia.

Kartagener's syndrome, originally described as situs inversus, bronchiectasis, and sinusitis, has recently been demonstrated to be the result of a genetic defect manifest in structural and functional abnormalities of cilia. The absence of dynein arms in the cilia of patients with Kartagener's syndrome has been found be several investigators, utilizing electron microscopy. The cilia of four siblings, two with the syndrome and two without it, were studied by this method. The siblings with Kartagener's syndrome had specific abnormalities of the cilia and the normal siblings did not. The pathophysiology of the disease is discussed and applied to the evaluation and management of patients with Kartagener's syndrome and the immotile cilia syndrome.

Adolescent↗
PubMed1990

Identification of a group of novel membrane proteins unique to chemosensory cilia of olfactory receptor cells.

We have used a library of monoclonal antibodies (mAbs) against chemosensory cilia of the olfactory epithelium of Rana catesbeiana to identify proteins that are unique to the ciliary membrane. Five different antibodies (mAb 8, 26, 34, 42/45, and 43) identify novel proteins in olfactory cilia that are not detected in olfactory nerve membranes, nonchemosensory cilia from respiratory epithelium, or membranes from brain, heart, liver, kidney, and lung. Deglycosylation of olfactory cilia with endoglycosidase H shows that most of these antibodies (mAb 8, 42/45, 43, and possibly 26) react with antigenic determinants comprised partially or entirely of carbohydrate, while only one (mAb 34) recognizes an 87-kDa protein that is resistant to endoglycosidase H treatment. Furthermore, a 59-kDa glycoprotein visualized by mAb 8 exists as membrane-associated oligomers connected via intermolecular disulfide bonds. These proteins, tagged with distinct high-mannose-containing carbohydrate moieties and found only in chemosensory cilia of olfactory receptor cells, may be involved in odorant recognition and/or olfactory transduction.

Animals↗
PubMed2004

Ultrastructural changes in the cilia of experimental mice.

Mice lacking dynein arms in the cilia were examined; the strain was obtained by inactivation of dynein heavy chain gene in chromosome 7. The cilia of these mice were examined by electron microscopy and compared to the cilia of random-bred mice. No statistically significant differences or typical disorders in the outer or inner dynein arms were detected. The number of inner dynein arms was lower, in some cilia secondary changes presenting as swelling of the outer part of the ciliary membrane or formation of complex cilia were seen.

Animals↗
PubMed2006

Regulation of primary cilia formation and left-right patterning in zebrafish by a noncanonical Wnt signaling mediator, duboraya.

Primary cilia are microtubule-based organelles that project from the surface of nearly every animal cell. Although important functions of primary cilia in morphogenesis and tissue homeostasis have been identified, the mechanisms that control the formation of primary cilia are not understood. Here we characterize a zebrafish gene, termed duboraya (dub), that is essential for ciliogenesis. Knockdown of dub in zebrafish embryos results in both defects in primary cilia formation in Kupffer's vesicle and randomization of left-right organ asymmetries. We show that, at the molecular level, the function of dub in ciliogenesis is regulated by phosphorylation, which in turn depends on Frizzled-2-mediated noncanonical Wnt signaling. We also provide evidence that, at the cellular level, dub function is essential for actin organization in the cells lining Kupffer's vesicle. Taken together, our findings identify a molecular factor that links noncanonical Wnt signaling with the control of left-right axis specification, and provide an entry point for analyzing the mechanisms that regulate primary cilia formation.

Animals↗
PubMed1977

The immotile-cilia syndrome. A congenital ciliary abnormality as an etiologic factor in chronic airway infections and male sterility.

We investigated six men and a woman suspected of suffering from congenital immotility of cilia. All had chronic airway infections, and the men had immotile spermatozoa. The woman and three men had Kartagener's syndrome. The investigations included measurements of the mucociliary transport in the lower airways and ultrastructural studies of the sperm tails or respiratory cilia (or both). Mucociliary transport was significantly delayed. Sperm tails lacked dynein arms in five patients. Respiratory cilia from the women and two men lacked dynein arms and were irregularly oriented. The results support the hypothesis that a congenital defect in the cilia and sperm tails will cause chronic respiratory-tract infections and male sterility--the immotile-cilia syndrome. In about half these patients there will also be a situs inversus--i.e., Kartagener's syndrome.

Adult↗
PubMed2004

Bardet-Biedl syndrome type 4 (BBS4)-null mice implicate Bbs4 in flagella formation but not global cilia assembly.

The functions of the proteins encoded by the Bardet-Biedl syndrome (BBS) genes are unknown. Mutations in these genes lead to the pleiotropic human disorder BBS, which is characterized by obesity, retinopathy, polydactyly, renal and cardiac malformations, learning disabilities, and hypogenitalism. Secondary features include diabetes mellitus and hypertension. Recently, it has been suggested that the BBS phenotypes are the result of a lack of cilia formation or function. In this study, we show that mice lacking the Bbs4 protein have major components of the human phenotype, including obesity and retinal degeneration. We show that Bbs4-null mice develop both motile and primary cilia, demonstrating that Bbs4 is not required for global cilia formation. Interestingly, male Bbs4-null mice do not form spermatozoa flagella, and BBS4 retinopathy involves apoptotic death of photoreceptors, the primary ciliated cells of the retina. These mutation data demonstrate a connection between the function of a BBS protein and cilia. To further evaluate an association between cilia and BBS, we performed homology comparisons of BBS proteins in model organisms and find that BBS proteins are specifically conserved in ciliated organisms.

Animals↗
PubMed2002

A proteomic analysis of human cilia: identification of novel components.

Cilia play an essential role in protecting the respiratory tract by providing the force necessary for mucociliary clearance. Although the major structural components of human cilia have been described, a complete understanding of cilia function and regulation will require identification and characterization of all ciliary components. Estimates from studies of Chlamydomonas flagella predict that an axoneme contains > or = 250 proteins. To identify all the components of human cilia, we have begun a comprehensive proteomic analysis of isolated ciliary axonemes. Analysis by two-dimensional (2-D) PAGE resulted in a highly reproducible 2-D map consisting of over 240 well resolved components. Individual protein spots were digested with trypsin and sequenced using liquid chromatography/tandem mass spectrometry (LC/MS/MS). Peptide matches were obtained to 38 potential ciliary proteins by this approach. To identify ciliary components not resolved by 2-D PAGE, axonemal proteins were separated on a one-dimensional gel. The gel lane was divided into 45 individual slices, each of which was analyzed by LC/MS/MS. This experiment resulted in peptide matches to an additional 110 proteins. In a third approach, preparations of isolated axonemes were digested with Lys-C, and the resulting peptides were analyzed directly by LC/MS/MS or by multidimensional LC/MS/MS, leading to the identification of a further 66 proteins. Each of the four approaches resulted in the identification of a subset of the proteins present. In total, sequence data were obtained on over 1400 peptides, and over 200 potential axonemal proteins were identified. Peptide matches were also obtained to over 200 human expressed sequence tags. As an approach to validate the mass spectrometry results, additional studies examined the expression of several identified proteins (annexin I, sperm protein Sp17, retinitis pigmentosa protein RP1) in cilia or ciliated cells. These studies represent the first proteomic analysis of the human ciliary axoneme and have identified many potentially novel components of this complex organelle.

Annexin A1↗
PubMed1962

Centrioles and the formation of rudimentary cilia by fibroblasts and smooth muscle cells.

Cells from a variety of sources, principally differentiating fibroblasts and smooth muscle cells from neonatal chicken and mammalian tissues and from organ cultures of chicken duodenum, were used as materials for an electron microscopic study on the formation of rudimentary cilia. Among the differentiating tissues many cells possessed a short, solitary cilium, which projected from one of the cell's pair of centrioles. Many stages evidently intermediate in the fashioning of cilium from centriole were encountered and furnished the evidence from which a reconstruction of ciliogenesis was attempted. The whole process may be divided into three phases. At first a solitary vesicle appears at one end of a centriole. The ciliary bud grows out from the same end of the centriole and invaginates the sac, which then becomes the temporary ciliary sheath. During the second phase the bud lengthens into a shaft, while the sheath enlarges to contain it. Enlargement of the sheath is effected by the repeated appearance of secondary vesicles nearby and their fusion with the sheath. Shaft and sheath reach the surface of the cell, where the sheath fuses with the plasma membrane during the third phase. Up to this point, formation of cilia follows the classical descriptions in outline. Subsequently, internal development of the shaft makes the rudimentary cilia of the investigated material more like certain non-motile centriolar derivatives than motile cilia. The pertinent literature is examined, and the cilia are tentatively assigned a non-motile status and a sensory function.

Animals↗
PubMed1999

Kinesin-II is preferentially targeted to assembling cilia and is required for ciliogenesis and normal cytokinesis in Tetrahymena.

We cloned two genes, KIN1 and KIN2, encoding kinesin-II homologues from the ciliate Tetrahymena thermophila and constructed strains lacking either KIN1 or KIN2 or both genes. Cells with a single disruption of either gene showed partly overlapping sets of defects in cell growth, motility, ciliary assembly, and thermoresistance. Deletion of both genes resulted in loss of cilia and arrests in cytokinesis. Mutant cells were unable to assemble new cilia or to maintain preexisting cilia. Double knockout cells were not viable on a standard medium but could be grown on a modified medium on which growth does not depend on phagocytosis. Double knockout cells could be rescued by transformation with a gene encoding an epitope-tagged Kin1p. In growing cells, epitope-tagged Kin1p preferentially accumulated in cilia undergoing active assembly. Kin1p was also detected in the cell body but did not show any association with the cleavage furrow. The cell division arrests observed in kinesin-II knockout cells appear to be induced by the loss of cilia and resulting cell paralysis.

Animals↗
PubMed2001

Polaris, a protein involved in left-right axis patterning, localizes to basal bodies and cilia.

Mutations in Tg737 cause a wide spectrum of phenotypes, including random left-right axis specification, polycystic kidney disease, liver and pancreatic defects, hydrocephalus, and skeletal patterning abnormalities. To further assess the biological function of Tg737 and its role in the mutant pathology, we identified the cell population expressing Tg737 and determined the subcellular localization of its protein product called Polaris. Tg737 expression is associated with cells possessing either motile or immotile cilia and sperm. Similarly, Polaris concentrated just below the apical membrane in the region of the basal bodies and within the cilia or flagellar axoneme. The data suggest that Polaris functions in a ciliogenic pathway or in cilia maintenance, a role supported by the loss of cilia on the ependymal cell layer in ventricles of Tg737(orpk) brains and by the lack of node cilia in Tg737(Delta2-3betaGal) mutants.

Animals↗
PubMed2003

XBX-1 encodes a dynein light intermediate chain required for retrograde intraflagellar transport and cilia assembly in Caenorhabditis elegans.

Intraflagellar transport (IFT) is a process required for flagella and cilia assembly that describes the dynein and kinesin mediated movement of particles along axonemes that consists of an A and a B complex, defects in which disrupt retrograde and anterograde transport, respectively. Herein, we describe a novel Caenorhabditis elegans gene, xbx-1, that is required for retrograde IFT and shares homology with a mammalian dynein light intermediate chain (D2LIC). xbx-1 expression in ciliated sensory neurons is regulated by the transcription factor DAF-19, as demonstrated previously for genes encoding IFT complex B proteins. XBX-1 localizes to the base of the cilia and undergoes anterograde and retrograde movement along the axoneme. Disruption of xbx-1 results in cilia defects and causes behavioral abnormalities observed in other cilia mutants. Analysis of cilia in xbx-1 mutants reveals that they are shortened and have a bulb like structure in which IFT proteins accumulate. The role of XBX-1 in IFT was further confirmed by analyzing the effect that other IFT mutations have on XBX-1 localization and movement. In contrast to other IFT proteins, retrograde XBX-1 movement was detected in complex A mutants. Our results suggest that the DLIC protein XBX-1 functions together with the CHE-3 dynein in retrograde IFT, downstream of the complex A proteins.

Animals↗
PubMed1994

Effect of halothane on cilia beat frequency of ciliated human respiratory epithelium in vitro.

The effect of halothane on human ciliated nasal epithelium was studied in vitro. Samples from 24 healthy adult volunteers were exposed to halothane in varying concentrations and cilia beat frequency was measured using the transmitted light technique. Mean cilia beat frequency was measured at 30-min intervals. There was a significant decrease in cilia beat frequency at 2 h in samples that were exposed to halothane (mean 8.4 (SD 2.5) Hz, 9.18 (2.6) Hz and 6.99 (4.9) Hz) compared with air (10.8 (2.7) Hz, 11.6 (2.1) Hz and 12.1 (2.3) Hz) (P < 0.01). The coefficient of variation of cilia beat frequency measurements increased after exposure to halothane. There was no change in the cilia beat frequency of controls exposed to air over a 3-h period.

Adult↗
PubMed1996

Effects of morphine on human nasal cilia beat frequency in vitro.

Using human nasal cytological brushings, we have investigated the effects of morphine on ciliary function by measurement of cilia beat frequency in vitro, and we have also determined opioid receptor binding in these specimens. We obtained ciliated samples from seven volunteers, and measured cilia beat frequency using the transmitted light technique during exposure to morphine 10 mumol litre-1 for 4 h. Mean cilia beat frequency of the samples exposed to morphine was 11.1 (95% confidence interval 10.9-11.5) Hz and that of the controls 11.3 (11.1-11.7) Hz. There was no significant effect of morphine on human cilia beat frequency in vitro (MANOVA for repeated measures and nested, F = 0.61, P = 0.66). In a separate study, we obtained nasal brushings from 20 patients and measured the binding of the opioid antagonist tritiated diprenorphine ([3H]DPN). Mean disintegrations per minute (dpm) for total and non-specific binding were 9036 (8105-9967) dpm and 9130 (8054-10206) dpm, respectively. These values did not differ significantly (paired t test, t = 0.22, P = 0.83). We conclude that morphine had no effect on cilia beat frequency in vitro and we were unable to demonstrate any significant numbers of opioid receptors on nasal ciliated epithelium.

Adult↗
PubMed2004

The autosomal recessive polycystic kidney disease protein is localized to primary cilia, with concentration in the basal body area.

Recent evidence suggests that structural and functional abnormalities of primary cilia in kidney epithelia are associated with mouse and human autosomal dominant polycystic kidney disease. To determine whether fibrocystin/polyductin/tigmin (FPC), the protein product encoded by the PKHD1 gene that is responsible for autosomal recessive polycystic kidney disease among human subjects, is also a component of primary cilia in the kidney, antipeptide antibodies to the carboxyl-terminal intracellular domain and amino-terminal extracellular domain of FPC were generated and were characterized with immunoblotting and immuno-light and -electron microscopy. Immunolocalization in normal kidney tissue sections and cultured kidney cells demonstrated that FPC was localized to the primary cilia and concentrated on the basal bodies in both kidney tissue sections and cultured kidney cells. The FPC expression pattern was not altered in kidney cells with Pkd1 mutations. These findings suggest that FPC is a functional and/or structural component of primary cilia in kidney tubular cells. It is proposed that the pathogenesis of autosomal recessive polycystic kidney disease is linked to the dysfunction of primary cilia.

Animals↗
PubMed1990

Localization of the sea urchin Spec3 protein to cilia and Golgi complexes of embryonic ectoderm cells.

Expression of the Spec3 gene of Strongylocentrotus purpuratus is associated with ectodermal ciliogenesis. An antiserum was raised against the amino terminus of the deduced Spec3 amino acid sequence and used for immunofluorescent staining. Cilia and an apical structure at the base of the stained cilium of each ectodermal cell stained intensely in gastrula and later stage embryos. Microtubule-depolymerizing agents dispersed the concentrated spot of apical staining, suggesting a localization of Spec3 antigen to the Golgi complex. Immunogold electron microscopy confirmed the localization of Spec3 antigen on cilia and in the Golgi complex. Spec3 antigen showed a diffuse punctate staining pattern in the ectodermal cytoplasm of hatching blastula when Spec3 transcripts are most prevalent, suggesting that after synthesis, Spec3 is sequestered in the Golgi complex before appearing on cilia. Whereas the predicted Mr of the Spec3 protein is 21,600, immunoblotting with S. purpuratus proteins indicated that a Spec3 antigen was concentrated in cilia and migrated as an SDS-resistant aggregate of Mr approximately 350,000. Spec3 is also concentrated in cilia of Lytechinus pictus but the protein migrated with an Mr approximately 23,000 in this species. The S. purpuratus Spec3 antigen remains associated with the ciliary axoneme after extraction of membrane proteins.

Amino Acid Sequence↗
PubMedDate not supplied

Use of a dermal biopsy punch for removal of ectopic cilia in dogs: 19 cases.

OBJECTIVE: To evaluate the use of a dermal biopsy punch for accurate and quick removal of ectopic cilia in dogs. ANIMALS STUDIED: This study reports the treatment of ectopic cilia detected in 12 dogs during the period from June 2002 to December 2004. Five cases were affected with ectopic cilia in the right eye, and five in the left eye, with two cases affected bilaterally. Nineteen ectopic cilia were detected in 12 dogs. PROCEDURE: The technique described in this study consists of using a 2-3-mm skin biopsy punch with the aid of an operating microscope. RESULTS: No recurrence was noted in any of the cases. The presurgical blepharospasm due to the presence of the cilia resolved as well as uneventful corneal healing of any associated corneal erosions or ulcers. CONCLUSIONS: This method offers a simple, practical alternative to the traditional scalpel procedure as described in the veterinary ophthalmic literature.

Animals↗
PubMed2003

Presence of Ca2+-dependent K+ channels in chemosensory cilia support a role in odor transduction.

Olfactory receptor neurons (ORNs) respond to odorants with changes in the action potential firing rate. Excitatory responses, consisting of firing increases, are mediated by a cyclic AMP cascade that leads to the activation of cationic nonselective cyclic nucleotide-gated (CNG) channels and Ca2+-dependent Cl- (ClCa) channels. This process takes place in the olfactory cilia, where all protein components of this cascade are confined. ORNs from various vertebrate species have also been shown to generate inhibitory odor responses, expressed as decreases in action potential discharges. Odor inhibition appears to rely on Ca2+-dependent K+ (KCa) channels, but the underlying transduction mechanism remains unknown. If these channels are involved in odor transduction, they are expected to be present in the olfactory cilia. We found that a specific antibody against a large conductance KCa recognized a protein of approximately 116 kDa in Western blots of purified rat olfactory ciliary membranes. Moreover, the antibody labeled ORN cilia in isolated ORNs from rat and toad (Caudiverbera caudiverbera). In addition, single-channel recordings from inside-out membrane patches excised from toad chemosensory cilia showed the presence of 4 different types of KCa channels, with unitary conductances of 210, 60, 12, and 29 and 60 pS, high K+-selectivity, and Ca2+ sensitivities in the low micromolar range. Our work demonstrates the presence of K+ channels in the ORN cilia and supports their participation in odor transduction.

Animals↗
PubMed1988

The propulsion of mucus by cilia.

The presence of cilia on epithelia of the respiratory tract was reported more than 150 yr ago, and the two-layer model of mucus transport was put forward more than 50 yr ago. However, it is only in the last 10 yr or so that the motion of mucus-propelling cilia of the mammalian respiratory system has been adequately described, and fluid dynamic studies have developed far enough to allow descriptions of the mechanisms by which ciliary movement is coupled to mucus transport. In this review, scientific developments on the study of cilia and mucus, and interactions between them, are drawn together to further understanding of mucociliary clearance mechanisms of the respiratory tract. The study of the cilia incorporates a discussion of the internal mechanics and biochemistry of the ciliary axoneme, the physical principles of the beat pattern, and the (weak) metachronal coordination of cilia in the lung. Mucus rheology plays a central role in mucociliary transport with the rheologic properties of the mucus determining the effective functioning of this clearance mechanism. Theoretical models provide information on the mechanical principles of the beat pattern as well as providing reliable estimates of the transport rates. Although airflow is not thought to contribute to mucus transport in the normal state, high frequency ventilation and coughing may make significant contributions.

Animals↗