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Proceedings of the American Thoracic... Sep 2011Primary ciliary dyskinesia (PCD) is a rare genetic disorder of ciliary structure and function. The diagnosis can be challenging, particularly when using nongenetic... (Review)
Review
Primary ciliary dyskinesia (PCD) is a rare genetic disorder of ciliary structure and function. The diagnosis can be challenging, particularly when using nongenetic assays. The "gold standard" diagnostic test is ultrastructural analysis of respiratory cilia obtained by nasal scrape or brush biopsy. A few specialized centers use high-speed videomicroscopy to examine ciliary beat. Certain beat patterns correlate with ultrastructural defects, and, in some cases, subtle alterations in beat pattern can be seen when ultrastructure is normal. Recent studies have shown that nasal nitric oxide (NO) is very low in patients with PCD compared with healthy control subjects; therefore, this assay may be a useful screening or adjunctive test for PCD. Because acute respiratory illnesses may yield alterations in ciliary ultrastructure, ciliary beat, and nasal NO values, these tests should be performed during a stable baseline period. Identification of an array of PCD genes has provided the opportunity for making a definitive genetic diagnosis for PCD in some cases. All of these approaches have a role in diagnosing PCD. For example, PCD has been confirmed by identifying disease-causing mutations in a heavy dynein chain gene in individuals with normal ciliary ultrastructure but subtle defects in ciliary beat and low nasal NO. Priorities to improve nongenetic diagnostic capability include standardization of nasal NO as a screening test and the development of specialized centers using uniform approaches for the analysis of ciliary ultrastructure and ciliary beat pattern. Another chapter in this issue (see Zariwala and colleagues, pp. 430) addresses the progress toward improved capabilities for definitive genetic testing.
Topics: Axoneme; Biomarkers; Cilia; Dyneins; Humans; Kartagener Syndrome; Microscopy, Electron; Microscopy, Video; Nasal Cavity; Nitric Oxide
PubMed: 21926395
DOI: 10.1513/pats.201103-028SD -
JCI Insight May 2023Leber congenital amaurosis (LCA) is a group of inherited retinal diseases characterized by early-onset, rapid loss of photoreceptor cells. Despite the discovery of a...
Leber congenital amaurosis (LCA) is a group of inherited retinal diseases characterized by early-onset, rapid loss of photoreceptor cells. Despite the discovery of a growing number of genes associated with this disease, the molecular mechanisms of photoreceptor cell degeneration of most LCA subtypes remain poorly understood. Here, using retina-specific affinity proteomics combined with ultrastructure expansion microscopy, we reveal the structural and molecular defects underlying LCA type 5 (LCA5) with nanoscale resolution. We show that LCA5-encoded lebercilin, together with retinitis pigmentosa 1 protein (RP1) and the intraflagellar transport (IFT) proteins IFT81 and IFT88, localized at the bulge region of the photoreceptor outer segment (OS), a region crucial for OS membrane disc formation. Next, we demonstrate that mutant mice deficient in lebercilin exhibited early axonemal defects at the bulge region and the distal OS, accompanied by reduced levels of RP1 and IFT proteins, affecting membrane disc formation and presumably leading to photoreceptor death. Finally, adeno-associated virus-based LCA5 gene augmentation partially restored the bulge region, preserved OS axoneme structure and membrane disc formation, and resulted in photoreceptor cell survival. Our approach thus provides a next level of assessment of retinal (gene) therapy efficacy at the molecular level.
Topics: Animals; Mice; Leber Congenital Amaurosis; Axoneme; Eye Proteins; Photoreceptor Cells
PubMed: 37071472
DOI: 10.1172/jci.insight.169162 -
Cold Spring Harbor Perspectives in... Aug 2017The cilium is an elongated and continuous structure that spans two major subcellular domains. The cytoplasmic domain contains a short centriole, which serves to nucleate... (Review)
Review
The cilium is an elongated and continuous structure that spans two major subcellular domains. The cytoplasmic domain contains a short centriole, which serves to nucleate the main projection of the cilium. This projection, known as the axoneme, remains separated from the cytoplasm by a specialized gatekeeping complex within a ciliary subdomain called the transition zone. In this way, the axoneme is compartmentalized. Intriguingly, however, this general principle of cilium biology is altered in the sperm cells of many animals, which instead contain a cytoplasmic axoneme domain. Here, we discuss the hypothesis that the formation of specialized sperm giant centrioles and cytoplasmic cilia is mediated by the migration of the transition zone from its typical location as part of a structure known as the annulus and examine the intrinsic properties of the transition zone that may facilitate its migratory behavior.
Topics: Animals; Axoneme; Centrioles; Cilia; Humans
PubMed: 28108487
DOI: 10.1101/cshperspect.a028142 -
Current Opinion in Microbiology Aug 2010Flagellar movement in Giardia, a common intestinal parasitic protist, is crucial to its survival in the host. Each axoneme is unique in possessing a long, cytoplasmic... (Review)
Review
Flagellar movement in Giardia, a common intestinal parasitic protist, is crucial to its survival in the host. Each axoneme is unique in possessing a long, cytoplasmic portion as well as a membrane-bound portion. Intraflagellar transport (IFT) is required for the assembly of membrane-bound regions, yet the cytoplasmic regions may be assembled by IFT-independent mechanisms. Steady-state axoneme length is maintained by IFT and by intrinsic and active microtubule dynamics. Following mitosis and before their segregation, giardial flagella undergo a multigenerational division cycle in which the parental eight flagella migrate and reposition to different cellular locations; eight new flagella are assembled de novo. Each daughter cell thus inherits four mature and four newly synthesized flagella.
Topics: Axoneme; Biological Transport; Cell Division; Flagella; Giardia; Giardiasis; Humans; Intestines
PubMed: 20580308
DOI: 10.1016/j.mib.2010.05.014 -
PLoS Biology Mar 2024Cilia play critical roles in cell signal transduction and organ development. Defects in cilia function result in a variety of genetic disorders. Cep290 is an...
Cilia play critical roles in cell signal transduction and organ development. Defects in cilia function result in a variety of genetic disorders. Cep290 is an evolutionarily conserved ciliopathy protein that bridges the ciliary membrane and axoneme at the basal body (BB) and plays critical roles in the initiation of ciliogenesis and TZ assembly. How Cep290 is maintained at BB and whether axonemal and ciliary membrane localized cues converge to determine the localization of Cep290 remain unknown. Here, we report that the Cep131-Cep162 module near the axoneme and the Cby-Fam92 module close to the membrane synergistically control the BB localization of Cep290 and the subsequent initiation of ciliogenesis in Drosophila. Concurrent deletion of any protein of the Cep131-Cep162 module and of the Cby-Fam92 module leads to a complete loss of Cep290 from BB and blocks ciliogenesis at its initiation stage. Our results reveal that the first step of ciliogenesis strictly depends on cooperative and retroactive interactions between Cep131-Cep162, Cby-Fam92 and Cep290, which may contribute to the complex pathogenesis of Cep290-related ciliopathies.
Topics: Animals; Basal Bodies; Cognition; Cues; Axoneme; Cilia; Drosophila
PubMed: 38442096
DOI: 10.1371/journal.pbio.3002330 -
Archives of Biochemistry and Biophysics Jun 2011Recent evidence has revealed that the dynein motors and highly conserved signaling proteins are localized within the ciliary 9+2 axoneme. One key mechanism for... (Review)
Review
Recent evidence has revealed that the dynein motors and highly conserved signaling proteins are localized within the ciliary 9+2 axoneme. One key mechanism for regulation of motility is phosphorylation. Here, we review diverse evidence, from multiple experimental organisms, that ciliary motility is regulated by phosphorylation/dephosphorylation of the dynein arms through kinases and phosphatases that are anchored immediately adjacent to their axonemal substrates.
Topics: Animals; Axoneme; Cilia; Conserved Sequence; Humans; Movement; Phosphoric Monoester Hydrolases; Protein Kinases
PubMed: 21513695
DOI: 10.1016/j.abb.2011.04.003 -
Nature Structural & Molecular Biology May 2022A pair of extensively modified microtubules form the central apparatus (CA) of the axoneme of most motile cilia, where they regulate ciliary motility. The external...
A pair of extensively modified microtubules form the central apparatus (CA) of the axoneme of most motile cilia, where they regulate ciliary motility. The external surfaces of both CA microtubules are patterned asymmetrically with large protein complexes that repeat every 16 or 32 nm. The composition of these projections and the mechanisms that establish asymmetry and longitudinal periodicity are unknown. Here, by determining cryo-EM structures of the CA microtubules, we identify 48 different CA-associated proteins, which in turn reveal mechanisms for asymmetric and periodic protein binding to microtubules. We identify arc-MIPs, a novel class of microtubule inner protein, that bind laterally across protofilaments and remodel tubulin structure and lattice contacts. The binding mechanisms utilized by CA proteins may be generalizable to other microtubule-associated proteins. These structures establish a foundation to elucidate the contributions of individual CA proteins to ciliary motility and ciliopathies.
Topics: Axoneme; Cilia; Microtubule-Associated Proteins; Microtubules; Tubulin
PubMed: 35578023
DOI: 10.1038/s41594-022-00770-2 -
Medecine Sciences : M/S Nov 2014Cilia and flagella are essential organelles in most eukaryotes including human beings. In this review, we will discuss the mode of assembly of these complex organelles... (Review)
Review
Cilia and flagella are essential organelles in most eukaryotes including human beings. In this review, we will discuss the mode of assembly of these complex organelles that depends on a dynamic process called intraflagellar transport or IFT. IFT delivers structural elements at the distal end of the cilium where assembly takes place, thereby allowing the growth of the organelle. We next discuss the different models for control of cilium length and their alterations in ciliopathies, genetic diseases associated to ciliary defects.
Topics: Animals; Axonemal Dyneins; Axoneme; Biological Transport; Cell Movement; Chlamydomonas reinhardtii; Cilia; Ciliary Motility Disorders; Eukaryotic Cells; Flagella; Humans; Microtubules; Models, Biological; Trypanosoma brucei brucei; Tubulin
PubMed: 25388576
DOI: 10.1051/medsci/20143011008 -
Cytoskeleton (Hoboken, N.J.) Apr 2010Axonemal dyneins have been demonstrated to monitor the mechanical state of the axoneme and must also alter activity in response to various signaling pathways. The... (Review)
Review
Axonemal dyneins have been demonstrated to monitor the mechanical state of the axoneme and must also alter activity in response to various signaling pathways. The central pair/radial spoke systems are clearly involved in controlling inner dynein arm function; however, the mechanisms by which the outer dynein arm transduces regulatory signals appear quite distinct at the molecular level. In Chlamydomonas, these regulatory components include thioredoxins involved in response to redox changes, molecules that tether the gamma heavy-chain motor unit to the A-tubule of the outer doublet and a Ca(2+)-binding protein that controls the structure of the gamma heavy-chain N-terminal domain. Together, these studies now suggest that the gamma heavy chain acts as a key regulatory node for controlling outer arm function in response to alterations in curvature and ligand binding. Furthermore, they allow us to propose a testable molecular mechanism by which altered Ca(2+) levels might lead to a change in ciliary waveform by controlling whether one heavy chain of outer arm dynein acts as a microtubule translocase or as an ATP-dependent brake that limits the amount of interdoublet sliding.
Topics: Animals; Axoneme; Calcium; Calcium Signaling; Dyneins
PubMed: 20186692
DOI: 10.1002/cm.20445 -
Nature Communications Jan 2024Radial spokes (RS) transmit mechanochemical signals between the central pair (CP) and axonemal dynein arms to coordinate ciliary motility. Atomic-resolution structures...
Radial spokes (RS) transmit mechanochemical signals between the central pair (CP) and axonemal dynein arms to coordinate ciliary motility. Atomic-resolution structures of metazoan RS and structures of axonemal complexes in ependymal cilia, whose rhythmic beating drives the circulation of cerebrospinal fluid, however, remain obscure. Here, we present near-atomic resolution cryo-EM structures of mouse RS head-neck complex in both monomer and dimer forms and reveal the intrinsic flexibility of the dimer. We also map the genetic mutations related to primary ciliary dyskinesia and asthenospermia on the head-neck complex. Moreover, we present the cryo-ET and sub-tomogram averaging map of mouse ependymal cilia and build the models for RS1-3, IDAs, and N-DRC. Contrary to the conserved RS structure, our cryo-ET map reveals the lack of IDA-b/c/e and the absence of Tektin filaments within the A-tubule of doublet microtubules in ependymal cilia compared with mammalian respiratory cilia and sperm flagella, further exemplifying the structural diversity of mammalian motile cilia. Our findings shed light on the stepwise mammalian RS assembly mechanism, the coordinated rigid and elastic RS-CP interaction modes beneficial for the regulation of asymmetric ciliary beating, and also facilitate understanding on the etiology of ciliary dyskinesia-related ciliopathies and on the ependymal cilia in the development of hydrocephalus.
Topics: Male; Animals; Mice; Cilia; Semen; Axoneme; Microtubules; Cytoskeleton; Mammals
PubMed: 38191553
DOI: 10.1038/s41467-023-44577-1