Role Of Cilia Research Articles

Role of Cilia, Mucus, and Airway Surface Liquid in Mucociliary Dysfunction: Lessons from Mouse Models

Role of Cilia, Mucus, and Airway Surface Liquid in Mucociliary Dysfunction: Lessons from Mouse Models

Absence Makes the Wnt Go Stronger

Wnts are secreted lipoproteins that are important in developmental processes. In the canonical Wnt pathway, Wnt3a signaling stabilizes β-catenin, which enters the nucleus and leads to expression of Wnt-target genes. Cilia are cellular projections that contain a central core of microtubules, and some proteins that are found in cilia, such as Inversin (see the commentary by He), mediate Wnt signaling. Corbit et al . investigated a possible role for cilia in the regulation of canonical Wnt signaling by generating mice and mouse embryonic fibroblasts (MEFs) deficient in Kif3a , which encodes a protein necessary for the generation of cilia. Reporter assays showed that Kif3a –/– MEFs responded more strongly to Wnt3a than did Kif3a +/– MEFs, whereas both cell types showed similar levels of basal activity. Western blotting assays showed that whereas Wnt3a treatment of Kif3a +/– MEFs resulted in the accumulation of β-catenin, Kif3a –/– MEFs showed a similar abundance of stabilized β-catenin even in the absence of Wnt3a. Wnt activation of Frizzled receptors results in the phosphorylation of Dishevelled (Dvl), which promotes stabilization of β-catenin. The authors showed by Western blotting that Dvl was constitutively phosphorylated in Kif3a –/– MEFs and that this was blocked by inhibition of casein kinase I (CKI), a kinase previously implicated in Dvl phosphorylation. Treatment with the CKI inhibitor also prevented the hyperresponsiveness of Kif3a –/– MEFs to treatment with Wnt3a, as assessed by reporter assays. Immunofluorescence microscopy demonstrated that some Wnt pathway components, including β-catenin, are present in cilia. This study suggests that cilia play a role in inhibiting canonical Wnt signaling, which may have implications for diseases associated with abnormal cilia, such as polycystic kidney disease. K. C. Corbit, A. E. Shyer, W. E. Dowdle, J. Gaulden, V. Singla, J. F. Reiter, Kif3a constrains β-catenin-dependent Wnt signalling through dual ciliary and non-ciliary mechanisms. Nat. Cell Biol. 10 , 70-76 (2008). [PubMed] X. He, Cilia put a brake on Wnt signalling. Nat. Cell Biol . 10 , 11-13 (2008). [PubMed]

Cilia and Developmental Signaling

Recent studies have revealed unexpected connections between the mammalian Hedgehog (Hh) signal transduction pathway and the primary cilium, a microtubule-based organelle that protrudes from the surface of most vertebrate cells. Intraflagellar transport proteins, which are required for the construction of cilia, are essential for all responses to mammalian Hh proteins, and proteins required for Hh signal transduction are enriched in primary cilia. The phenotypes of different mouse mutants that affect ciliary proteins suggest that cilia may act as processive machines that organize sequential steps in the Hh signal transduction pathway. Cilia on vertebrate cells are likely to be important in additional developmental signaling pathways and are required for PDGF receptor alpha signaling in cultured fibroblasts. Cilia are not essential for either canonical or noncanonical Wnt signaling, although cell-type-specific modulation of cilia components may link cilia and Wnt signaling in some tissues. Because ciliogenesis in invertebrates is limited to a very small number of specialized cell types, the role of cilia in developmental signaling pathways is likely a uniquely vertebrate phenomenon.

Heterotaxia, Congenital Heart Disease, and Primary Ciliary Dyskinesia

The human heart is strikingly asymmetrical along the left-right body axis. If one begins with the position of the heart in the left chest, continues through asymmetrical venous drainage into the atria and asymmetrical orientation of the 2 anatomically and functionally distinct ventricles, and finally proceeds through the highly asymmetrical coil of semilunar valves and great vessels, the structure and function of the human heart are precisely aligned to the left-right axis. When cardiac asymmetries either fail to develop or align incorrectly relative to each other or relative to other organs, a plethora of congenital heart disease results. This group of heart diseases is called heterotaxy syndrome and represents both a difficult clinical challenge and a fascinating window into the biology underlying one of the most fundamental embryological processes, namely, the mechanism by which an organism establishes the 3 body axes. Positioning of organs along the left-right axis can be divided into 3 broad classes: situs solitus, in which all organs are positioned normally; situs inversus, in which there is mirror image reversal of all organs; and heterotaxy, in which there is any positioning of organs along the left-right axis differing from situs solitus and situs inversus (Figure). Pure situs inversus is found in 1 of 8500 in the general population and is usually not associated with intracardiac defects. In contrast, heterotaxy has a high degree of association with intracardiac defects. It has a reported incidence of 1 of 10 000 and is associated with at least 3% of cases of congenital heart disease.1 The anatomic spectrum of organ laterality. A, Situs solitus. B, Right atrial isomerism. The liver is midline, there are 2 eparterial bronchi, the position of the stomach and cardiac apex is indeterminate, and there is asplenia. C, Left atrial isomerism. The liver is midline, there …

Identification of BCAP, a new protein associated with basal bodies and centrioles

Cilia exert critical functions in numerous organisms, including that of cell motility, fluid transport and protozoan locomotion. Defects in this organelle can lead to lethal pathologies in humans, including primary ciliary dyskinesia. An understanding of the cilia formation process would lead to better characterization of defects involved in such pathologies. In the present study, we identified a gene encoding a novel human protein, BCAP for Basal body Centriole-Associated Protein, which shares homologies with a previously described protein, Outer Dense Fiber 2 (ODF2). ODF2, a major component of the sperm tail cytoskeleton, is required for the formation of mother centriole distal/subdistal appendages and the generation of primary cilia. Here, we show that the bcap gene contains 18 alternatively spliced exons and encodes five different isoforms, three long and two short ones. BCAP is preferentially expressed in cilia/flagella containing tissues. Moreover, its expression is correlated with cilia formation during mucociliary differentiation of human nasal epithelial cells. Using immunofluorescence analyses, BCAP was localized within basal bodies of ciliated cells and within centrioles of proliferating cells. In light of the several spliced isoforms of BCAP and the particular localization of the protein, BCAP isoforms could play distinct roles in cilia and in centrosomes.

Roles for cilia in bone cells?

Roles for cilia in bone cells?

The roles of cilia in developmental disorders and disease

Cilia are highly conserved organelles that have diverse motility and sensory functions. Recent discoveries have revealed that cilia also have crucial roles in cell signaling pathways and in maintaining cellular homeostasis. As such, defects in cilia formation or function have profound effects on the development of body pattern and the physiology of multiple organ systems. By categorizing syndromes that are due to cilia dysfunction in humans and from studies in vertebrate model organisms, molecular pathways that intersect with cilia formation and function have come to light. Here, we summarize an emerging view that in order to understand some complex developmental pathways and disease etiologies, one must consider the molecular functions performed by cilia.

IFTA-2 is a conserved cilia protein involved in pathways regulating longevity and dauer formation inCaenorhabditis elegans

Defects in cilia are associated with diseases and developmental abnormalities. Proper cilia function is required for sonic hedgehog and PDGFRalpha signaling in mammals and for insulin-like growth factor (IGF) signaling in Caenorhabditis elegans. However, the role of cilia in these pathways remains unknown. To begin addressing this issue, we are characterizing putative cilia proteins in C. elegans that are predicted to have regulatory rather than structural functions. In this report, we characterized the novel cilia protein T28F3.6 (IFTA-2, intraflagellar transport associated protein 2), which is homologous to the mammalian Rab-like 5 protein. We found that, unlike the intraflagellar transport (IFT) genes, disruption of ifta-2 does not result in overt cilia assembly abnormalities, nor did it cause chemotaxis or osmotic avoidance defects typical of cilia mutants. Rather, ifta-2 null mutants have an extended lifespan phenotype and are defective in dauer formation. Our analysis indicates that these phenotypes result from defects in the DAF-2 (insulin-IGF-1-like) receptor signaling pathway in ciliated sensory neurons. We conclude that IFTA-2 is not a ciliogenic protein but rather is a regulator of specific cilia signaling activities. Interestingly, a mammalian IFTA-2 homolog is also found in cilia, raising the possibility that its function has been conserved during evolution.

ADP-Ribosylation Factor-Like 3 Is Involved in Kidney and Photoreceptor Development

ADP-ribosylation factor-like 3 (Arl3) is a member of a small subfamily of G-proteins involved in membrane-associated vesicular and intracellular trafficking processes. Genetic studies in Leishmania have shown that the Arl3 homolog is essential for flagellum biogenesis. Mutations in a related human family member, Arl6, result in Bardet-Biedl syndrome in humans, which is characterized by genital, renal, and retinal abnormalities, obesity, and learning deficits. As part of our large-scale phenotypic screen, mice deficient for the Arl3 gene were generated and analyzed. Arl3 (-/-) mice were born at a sub-Mendelian ratio, were small and sickly, and had markedly swollen abdomens. These mutants failed to thrive, and all died by 3 weeks of age. The (-/-) mice exhibited abnormal development of renal, hepatic, and pancreatic epithelial tubule structures, which is characteristic of the renal-hepatic-pancreatic dysplasia found in autosomal recessive polycystic kidney disease. Absence of Arl3 was associated with abnormal epithelial cell proliferation and cyst formation. Moreover, mice lacking Arl3 exhibited photoreceptor degeneration as early as postnatal day 14. These results are the first to implicate Arl3 in a ciliary disease affecting the kidney, biliary tract, pancreas, and retina.

Ciliary Function and the Role of Cilia in Clearance

The lungs and the nasal passages are continually exposed to respiratory pathogens, toxins, and particulate matter, and have evolved a very effective defense system to protect themselves. Mucociliary clearance is an essential part of this defence and relies on appropriate interactions between the ciliated epithelium, the height of the periciliary fluid, and mucus. Mucus acts as a physical barrier, trapping inhaled particles and pathogens, whilst cilia move both the mucus layer and fluid in the underlying periciliary layer. These defenses may be disrupted by viral and bacterial infections, by inhaled toxins, and by inherited diseases such as primary ciliary dyskinesia and cystic fibrosis.

Mating worms and the cystic kidney: Caenorhabditis elegans as a model for renal disease

Polycystic kidney disease (PKD) is caused by a group of variably inherited human disorders that are major causes of end-stage renal disease in both children and adults. The genetic culprits responsible for autosomal-dominant PKD (ADPKD), the polycystins, have been identified, yet still little is known about the molecular mechanisms that result in the disease phenotype. Polycystin homologs have been isolated in the model genetic organism Caenorhabditis elegans and, interestingly, play a specific role in C. elegans male mating behavior. Despite the recruitment of the polycystins for divergent functions in worms and humans it appears that the fundamental molecular and genetic interactions of these genes are evolutionarily conserved. In addition, studies in the worm have contributed to an understanding of the emerging role for cilia in the function of the polycystin pathway, expanding a promising frontier in PKD research. C. elegans has also been used to identify a gene family which may have significance for understanding the formation and maintenance of renal tubules.

Functional characterization of the C. elegans nephrocystins NPHP-1 and NPHP-4 and their role in cilia and male sensory behaviors

Autosomal dominant polycystic kidney disease (ADPKD) and nephronophthisis (NPH) share two common features: cystic kidneys and ciliary localized gene products. Mutation in either the PKD1 or PKD2 gene accounts for 95% of all ADPKD cases. Mutation in one of four genes ( NPHP1-4) results in nephronophthisis. The NPHP1, NPHP2, PKD1, and PKD2 protein products (nephrocystin-1, nephrocystin-2 or inversin, polycystin-1, and polycystin-2, respectively) localize to primary cilia of renal epithelia. However, the relationship between the nephrocystins and polycystins, if any, is unknown. In the nematode Caenorhabditis elegans, the LOV-1 and PKD-2 polycystins localize to male-specific sensory cilia and are required for male mating behaviors. To test the hypothesis that ADPKD and NPH cysts arise from a common defect in cilia, we characterized the C. elegans homologs of NPHP1 and NPHP4. C. elegans nphp-1 and nphp-4 are expressed in a subset of sensory neurons. GFP-tagged NPHP-1 and NPHP-4 proteins localize to ciliated sensory endings of dendrites and colocalize with PKD-2 in male-specific sensory cilia. The cilia of nphp-1(ok500) and nphp-4(tm925) mutants are intact. nphp-1; nphp-4 double, but not single, mutant males are response defective. We propose that NPHP-1 and NPHP-4 proteins play important and redundant roles in facilitating ciliary sensory signal transduction.

Primary ciliary dyskinesia: a report from ATS 2001, May 18–23, San Francisco

Primary ciliary dyskinesia (PCD) is a genetic disorder of abnormal ciliary structure and function that leads to defective mucociliary clearance, resulting in oto-sino-pulmonary disease, and infertility. The disease is currently under intense investigation by a number of research groups worldwide. At the recent American Thoracic Society meeting in San Francisco in May 2001, two sessions focused on PCD; a symposium session on May 21 with several featured expert speakers was followed by a mini-symposium on Tuesday May 22, with one featured speaker and presentation of nine abstracts covering a range of research topics. Mattias Salathe (University of Miami, USA) and Stephen Brody (Washington University, St Louis, USA) chaired the symposium session. Presentations focused on the clinical spectrum of PCD, the genetics of PCD, a proteomics approach to detail the structure of cilia, the role of cilia in the embryology of situs laterality, and airway epithelial cell biology. The mini-symposium was chaired by Peadar Noone (University of North Carolina, USA) and Malcolm King (University of Alberta, USA) and included presentations on the use of PCD as a human disease model, accurate definition of the phenotype using clinical and cell biologic markers, and molecular studies. The latter reports ranged from isolation of a protein involved in ciliary structure and function to genetic studies using linkage analysis and the candidate gene approach. Clinicians and scientists alike displayed considerable interest at both sessions, and there were several lively question–answer sessions.

Determination of Left-Right Asymmetry: Role of Cilia and KIF3 Motor Proteins.

Heinz Valtin Editor, trendsetters Our bodies are asymmetrical: the heart, spleen, and pancreas reside on the left, whereas the gallbladder and most of the liver are on the right. When this asymmetry is reversed, the condition is called situs inversus. Human patients with a genetic disorder called

Primary ciliary dyskinesia

Most medical students can remember that Kartagener Syndrome is the association of situs inversus, bronchiectasis and sinusitis as a result of defective ciliary function. What is equally important but seldom remembered is that 50% of patients with primary ciliary dyskinesia (PCD) do not have situs inversus. It is these patients in whom the diagnosis of PCD, the universal term for this disorder, may be delayed. This has important implications because the early initiation of physiotherapy combined with aggressive treatment of acute respiratory infections can prevent deterioration in lung function. Recognition of the diagnosis of PCD also has implications for ENT intervention. In common with many paediatric diseases, an understanding of the normal anatomy and physiology enables a more complete understanding of the possible clinical presentation and complications of PCD. This article begins with a brief description of normal ciliary ultrastructure and the role of cilia in health.

The linking of extrinsic stimuli to behaviour: Roles of cilia in ciliates

The linking of extrinsic stimuli to behaviour: Roles of cilia in ciliates

Grand Rounds - Hammersmith Hospital Late presentation of Kartagener's syndrome Consequences of ciliary dysfunction

Primary ciliary dyskinesia provides a unique insight into the role of cilia in the human body. It is usually diagnosed in childhood, when prompt treatment of respiratory infections can minimise irreversible damage to the lungs. A 48 year old man presented with a four month history of cough productive of green sputum, a two month history of night sweats, and a two day history of left sided pleuritic chest pain. He had previously had recurrent chest infections, recurrent purulent rhinosinusitis, and had produced more than one cupful of sputum a day for many years. He smoked 20 cigarettes a day. On examination he had a fever (38°C), a regular pulse (100 beats/min), and blood pressure of 130/80 mm Hg. He was not clubbed. His apex beat was localised to the right fifth intercostal space and he had signs of consolidation in the left mid-zone. He had complete situs inversus viscerum. He had a haemoglobin concentration of 140 g/l and a peripheral leucocyte count of 11.8x109/l with 88% neutrophils. His erythrocyte sedimentation rate (34 mm in the first hour) and C reactive protein concentration (15 mg/l) were raised. Routine biochemistry tests gave normal results. Blood cultures were sterile but sputum culture grew Streptococcus pneumoniae. Culture was negative for acid fast bacilli. Chest radiography confirmed dextrocardia, with the aortic arch lying on the right side of the trachea (fig 1). The left lung had three lobes with consolidation in the middle lobe. A gastric air bubble was noted on the right side. The plain film showed no evidence of bronchiectasis but computed tomography of the chest after his pneumonia had resolved showed bronchiectasis in the left middle lobe and right lower lobe (fig 2). FIG 1 Chest radiograph showing dextrocardia with the aortic arch lying on the right side of the …

Recognition of Prey by Suctoria: The Role of Cilia

ABSTRACT. The interaction between the predator, Discophrya collini, and the prey, Tetrahymena pyriformis, was investigated in order to determine what prey factors(s) may be recognized, facilitating the feeding response of the suctorian predator. When viable, deciliated T. pyriformis were offered to starved D. collini, only 12% of the suctoria captured a ciliate compared to 98% when presented with ciliated T. pyriformis. Starved suctoria were also offered three types of tanned sheep erythrocytes used as artificial prey. After exposure to erythrocytes coated with sonicates of T. pyriformis, 16% of the D. collini displayed one or more attached erythrocytes but after incubation with erythrocytes coated with T. pyriformis cilia, 72% of the suctoria had tentacles with attached cells. No untreated, tanned erythrocytes were captured. When T. pyriformis were treated with ciliary antiserum and then offered to starved D. collini, the resulting capture rate was low (13%), but T. pyriformis treated with normal rabbit serum were captured at a rate comparable to controls (92%). These results suggest that the prey's cilia and/or their surface macromolecules may facilitate prey capture.

Mechanoelectrical transduction mediated through cilia in protists

Unicellular organisms respond to a variety of stimuli, such as light, touch, or chemical action. A Paramecium cell, which meets an obstacle, reverses the swimming direction and eventually resumes forward locomotion in a new direction. It has been a plausible assumption that the cilia are receptors as well as effectors. This view gains support by analogy: ciliary structures exist in various metazoan tissue specialized for stimulus sensation. A previous elegant hypothesis assumed that a ciliary mechanoreceptor employs the ciliary motile machine in reverse in that bending of the axoneme can generate a chemical signal. Recent electrophysiological studies in ciliates have contributed to a re-assessment of the role of cilia in mechanotransduction. This lecture summarizes some experimental evidence as to how the sensory function is organized in a ciliated cell.

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Mucociliary function is governed by cilia, mucus, and their interaction. To play their role in mucociliary function, cilia must be present in large number. It has been reported that the ciliary area is reduced in acute and chronic inflammations of the upper respiratory mucosa. However, quantitative observations of the ciliary area in these conditions have not been reported. In this study, ciliary areas of the maxillary turbinate infected with the B strain of Newcastle disease virus (NDV) were quantified with a scanning electron microscope and an image analyzer. The epithelial surface occupied by cilia was calculated by an image analyzer. The ciliary area was expressed as a percentage of the total area examined. Ninety 21-day-old chickens were inoculated intranasally with NDV. The ciliary area and mucociliary transport time were examined periodically. The ciliary area was reduced about 50% on day 5 and then recovered gradually to normal by day 21. The ciliary area was reduced by increasing amounts of inoculated virus. A negative correlation was noted between histopathologic severity and ciliary area. The mucociliary transport time in the NDV infected nasal mucosa increased as the percentage of the ciliary area decreased. In this study, reduction of the area occupied by cilia caused deceleration of nasal mucociliary transport. Quantitative analysis of the ciliary area can clarify the role of cilia in mucociliary dysfunction.