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Concept: Cilium

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Since the discovery that proteins mutated in different forms of polycystic kidney disease (PKD) are tightly associated with primary cilia, strong efforts have been made to define the role of this organelle in the pathogenesis of cyst formation. Cilia are filiform microtubular structures, anchored in the basal body and extending from the apical membrane into the tubular lumen. Early work established that cilia act as flow sensors, eliciting calcium transients in response to bending, which involve the two proteins mutated in autosomal dominant PKD (ADPKD), polycystin-1 and -2. Loss of cilia alone is insufficient to cause cyst formation. Nevertheless, a large body of evidence links flow sensing by cilia to aspects relevant for cyst formation such as cell polarity, Stat6- and mammalian target of rapamycin signalling. This review summarizes the current literature on cilia and flow sensing with respect to PKD and discusses how these findings intercalate with different aspects of cyst formation.

Concepts: Immune system, Kidney, Cell, Genetic disorder, Golgi apparatus, Cytoskeleton, Polycystic kidney disease, Cilium

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The primary cilium is a non-motile microtubule-based organelle that protrudes from the surface of most human cells and works as a cellular antenna to accept extracellular signals. Primary cilia assemble from the basal body during the resting stage (G0 phase) and simultaneously disassemble with cell cycle re-entry. Defective control of assembly or disassembly causes diverse human diseases including ciliopathy and cancer. To identify the effective compounds for studying primary cilium disassembly, we have screened 297 natural compounds and identified 18 and 17 primary cilium assembly and disassembly inhibitors, respectively. Among them, the application of KY-0120, identified as Brefeldin A, disturbed Dvl2- Plk1-mediated cilium disassembly via repression of the interaction of CK1e-Dvl2 and the expression of Plk1 mRNA. Therefore, our study may suggest useful compounds for studying the cellular mechanism of primary cilium disassembly to prevent ciliopathy and cancer.

Concepts: Cell nucleus, Cell, Cancer, Eukaryote, Organelle, Cilium, Ciliopathy, Antenna

51

Primary cilia are sensory organelles that protrude from the cell membrane. Defects in the primary cilium cause ciliopathy disorders, with retinal degeneration as a prominent phenotype. Here, we demonstrate that the retinal pigment epithelium (RPE), essential for photoreceptor development and function, requires a functional primary cilium for complete maturation and that RPE maturation defects in ciliopathies precede photoreceptor degeneration. Pharmacologically enhanced ciliogenesis in wild-type induced pluripotent stem cells (iPSC)-RPE leads to fully mature and functional cells. In contrast, ciliopathy patient-derived iPSC-RPE and iPSC-RPE with a knockdown of ciliary-trafficking protein remain immature, with defective apical processes, reduced functionality, and reduced adult-specific gene expression. Proteins of the primary cilium regulate RPE maturation by simultaneously suppressing canonical WNT and activating PKCδ pathways. A similar cilium-dependent maturation pathway exists in lung epithelium. Our results provide insights into ciliopathy-induced retinal degeneration, demonstrate a developmental role for primary cilia in epithelial maturation, and provide a method to mature iPSC epithelial cells for clinical applications.

Concepts: Protein, Gene, Cell, Organelle, Developmental biology, Stem cell, Cell biology, Cilium

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One of the hallmarks of multicellular organisms is the ability of their cells to trigger responses to the environment in a coordinated manner. In recent years primary cilia have been shown to be present as ‘antennae’ on almost all animal cells, and are involved in cell-to-cell signaling in development and tissue homeostasis; how this sophisticated sensory system arose has been little-studied and its evolution is key to understanding how sensation arose in the Animal Kingdom. Sponges (Porifera), one of the earliest evolving phyla, lack conventional muscles and nerves and yet sense and respond to changes in their fluid environment. Here we demonstrate the presence of non-motile cilia in sponges and studied their role as flow sensors.

Concepts: DNA, Cell, Bacteria, Biology, Organism, Ecology, Animal, Cilium

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Primary ciliary dyskinesia (PCD) is a rare autosomal recessive disease, caused by specific primary structural and/or functional abnormalities of the motile cilia, in contrast with the transitory abnormalities seen in secondary ciliary dyskinesia. Disease-causing mutations in at least 16 genes have already been identified. The true incidence of PCD may be higher than currently reported, because the diagnosis is challenging and often missed. For the confirmation of PCD, both ciliary motility as well as ciliary ultrastructure must be evaluated. An early and adequate diagnosis and therapy can theoretically prevent bronchiectasis. Measurement of nasal nitric oxide has some value as a screening test but cannot be performed in young children. In the respiratory tract epithelium, impaired mucociliary clearance leads to chronic and/or recurrent upper and lower respiratory tract infections. In up to 75 % of the patients, respiratory manifestations start in the newborn period, although the diagnosis is often missed at that time. During embryogenesis, nodal cilia, which are motile cilia, determine the correct lateralization of the organs. Dysfunction of these cilia leads to random lateralization and thus situs inversus in approximately 50 % of the patients with PCD. The tail of a spermatozoon has a structure similar to that of a motile cilium. Consequently, male infertility due to immotile spermatozoa is often part of the characteristics of PCD. Given the heterogeneity and the rarity of the disorder, therapy is not evidence-based. Many treatment schedules are proposed in analogy with the treatment for cystic fibrosis. CONCLUSION: Respiratory infections, situs inversus and male infertility are typical manifestations of PCD, a rare autosomal recessive disorder.

Concepts: Sperm, Cystic fibrosis, Respiratory system, Upper respiratory tract, Cilium, Situs inversus, Respiratory tract, Primary ciliary dyskinesia

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Human cilia were once thought merely to be important in respiratory mucociliary clearance, with primary ciliary dyskinesia (PCD) the sole manifestation of ciliary dysfunction. There are now known to be three types of cilia: primary, nodal and motile. Cilia are complex, likely involving more than 1000 gene products; in this review, recent advances in PCD genetics, and the potential relationships with genes causing other ciliopathies, are discussed. PCD is the most important respiratory disease, characterized by upper and lower airway infection and inflammation and disorders of laterality. Ciliary gene mutations are now known to cause single organ disease, as well as complex syndromes. The focus of the review is primarily PCD, in the context of the expanding ciliopathy spectrum. The authors consider the clinical situations in which ciliary disease should be considered, and the implications for specialist respiratory practice.

Concepts: DNA, Gene, Genetics, Cell, Genetic disorder, Biology, Cilium, Ciliopathy

27

Respiratory syncytial virus (RSV) is a major cause of respiratory disease. There are conflicting accounts of the response of human epithelial cells to RSV and a lack of data on its effect on ciliary function. Our aim was to study the early stages of RSV infection of primary human basal and ciliated cultures.Using high speed video microscopy, we found that ciliary beat frequency was unaffected by RSV infection over 72 hours, however, ciliary dyskinesia significantly (P<0.05) increased within 24 hours of infection. Transmission electron microscopy revealed that ultrastructural abnormalities were confined to ciliated cells, including increased cilia loss and mitochondrial damage. Confocal immunofluorescence microscopy showed RSV antigen gradually spread from the cell surface to the ciliary tip of infected cells over three days. Interestingly, ciliated cultures secreted fewer viruses than basal (progenitor) cell cultures and produced a chemokine response focused on recruitment of neutrophils.This study highlights differences in infection models and underscores the need to further to explore the role of ciliated cells in the establishment of RSV infection. Increased ciliary dyskinesia combined with ciliary loss and epithelial damage is likely to result in reduced mucociliary clearance early in the infective process.

Concepts: Protein, Cell, Bacteria, Eukaryote, Organelle, Cell biology, Human respiratory syncytial virus, Cilium

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How phosphoinositide metabolism is coupled to primary cilia physiology is poorly understood. Reporting recently in Developmental Cell, Chávez et al. (2015) and Garcia-Gonzalo et al. (2015) show that INPP5E-mediated phosphoinositide metabolism, which creates a specific phosphoinositide distribution, ensures proper protein trafficking and Hh signaling in primary cilia.

Concepts: DNA, Protein, Gene, Cell, Bacteria, Nutrition, Organism, Cilium

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The development of multicellular organisms requires the precisely coordinated regulation of an evolutionarily conserved group of signaling pathways. Temporal and spatial control of these signaling cascades is achieved through networks of regulatory proteins, segregation of pathway components in specific subcellular compartments, or both. In vertebrates, dysregulation of primary cilia function has been strongly linked to developmental signaling defects, yet it remains unclear whether cilia sequester pathway components to regulate their activation or cilia-associated proteins directly modulate developmental signaling events. To elucidate this question, we conducted an RNAi-based screen in Drosophila non-ciliated cells to test for cilium-independent loss-of-function phenotypes of ciliary proteins in developmental signaling pathways. Our results show no effect on Hedgehog signaling. In contrast, our screen identified several cilia-associated proteins as functioning in canonical Wnt signaling. Further characterization of specific components of Intraflagellar Transport complex A uncovered a cilia-independent function in potentiating Wnt signals by promoting β-catenin/Armadillo activity.

Concepts: Gene, Cell, Species, Developmental biology, Regulation, Cilium, Wnt signaling pathway, Ciliopathy

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The present article is a comparative, structural study of the lung of Polypterus senegalus and Erpetoichthys calabaricus, two species representative of the two genera that constitute the Polypteriformes. The lung of the two species is an asymmetric, bi-lobed organ that arises from a slit-like opening in the ventral side of the pharynx. The wall is organized into layers, being thicker in P. senegalus. The inner epithelium contains ciliated and non-ciliated bands. The latter constitute the respiratory surface and are wider in E. calabaricus. The air-blood barrier is thin and uniform in P. senegalus and thicker and irregular in E. calabaricus. In the two species, the ciliated areas contain ciliated cells, mucous cells and cells with lamellar bodies. Additionally, P. senegalus contains polymorphous granular cells (PGCs) and neuroendocrine cells (NECs) while E. calabaricus lacks PGCs but shows granular leukocytes and a different type of NEC. Interestingly, ciliated cells and secretory cells show a dual morphology in E. calabaricus indicating the presence of cellular subtypes and suggesting more complex secretory activity. Also in E. calabaricus, cilia show a novel doublet-membrane interaction that may control the displacement of the microtubule doublets. The subepithelium is a connective layer that appears thicker in P. senegalus and contains, in the two species, fibroblasts and granulocytes. The outer layer contains bundles of richly innervated striated muscle. This layer is likely involved in the control of lung motion. In the two species, smooth muscle cells constitute a limiting layer between the subepithelium and the striated muscle compartment. The role of this layer is unclear.

Concepts: Lung, Heart, Epithelium, Smooth muscle, Muscular system, Connective tissue, Cilium, Bichir