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https://www.readbyqxmd.com/read/28230057/ensemble-and-single-molecule-dynamics-of-ift-dynein-in-caenorhabditis-elegans-cilia
#1
Jona Mijalkovic, Bram Prevo, Felix Oswald, Pierre Mangeol, Erwin J G Peterman
Cytoplasmic dyneins drive microtubule-based, minus-end directed transport in eukaryotic cells. Whereas cytoplasmic dynein 1 has been widely studied, IFT dynein has received far less attention. Here, we use fluorescence microscopy of labelled motors in living Caenorhabditis elegans to investigate IFT-dynein motility at the ensemble and single-molecule level. We find that while the kinesin composition of motor ensembles varies along the track, the amount of dynein remains relatively constant. Remarkably, this does not result in directionality changes of cargo along the track, as has been reported for other opposite-polarity, tug-of-war motility systems...
February 23, 2017: Nature Communications
https://www.readbyqxmd.com/read/28217833/lengthening-primary-cilia-enhances-cellular-mechanosensitivity
#2
M Spasic, C R Jacobs
The primary cilium is a mechanosensor in a variety of mammalian cell types, initiating and directing intracellular signalling cascades in response to external stimuli. When primary cilia formation is disrupted, cells have diminished mechanosensitivity and an abrogated response to mechanical stimulation. Due to this important role, we hypothesised that increasing primary cilia length would enhance the downstream response and therefore, mechanosensitivity. To test this hypothesis, we increased osteocyte primary cilia length with fenoldopam and lithium and found that cells with longer primary cilia were more mechanosensitive...
February 20, 2017: European Cells & Materials
https://www.readbyqxmd.com/read/28215051/-pro-renin-receptor-atp6ap2-depletion-arrests-as4-1-cells-in-the-g0-g1-phase-thereby-increasing-formation-of-primary-cilia
#3
Heike Wanka, Philipp Lutze, Doreen Staar, Barbara Peters, Anica Morch, Lukas Vogel, Ravi Kumar Chilukoti, Georg Homuth, Jaroslaw Sczodrok, Inga Bäumgen, Jörg Peters
The (pro)renin receptor [(P)RR, ATP6AP2] is a multifunctional transmembrane protein that activates local renin-angiotensin systems, but also interacts with Wnt pathways and vacuolar H(+) -ATPase (V-ATPase) during organogenesis. The aim of this study was to characterize the role of ATP6AP2 in the cell cycle in more detail. ATP6AP2 down-regulation by siRNA in renal As4.1 cells resulted in a reduction in the rate of proliferation and a G0/G1 phase cell cycle arrest. We identified a number of novel target genes downstream of ATP6AP2 knock-down that were related to the primary cilium (Bbs-1, Bbs-3, Bbs-7, Rabl5, Ttc26, Mks-11, Mks-5, Mks-2, Tctn2, Nme7) and the cell cycle (Pierce1, Clock, Ppif)...
February 19, 2017: Journal of Cellular and Molecular Medicine
https://www.readbyqxmd.com/read/28213462/discovery-diagnosis-and-etiology-of-craniofacial-ciliopathies
#4
Elizabeth N Schock, Samantha A Brugmann
Seventy-five percent of congenital disorders present with some form of craniofacial malformation. The frequency and severity of these malformations makes understanding the etiological basis crucial for diagnosis and treatment. A significant link between craniofacial malformations and primary cilia arose several years ago with the determination that ∼30% of ciliopathies could be primarily defined by their craniofacial phenotype. The link between the cilium and the face has proven significant, as several new "craniofacial ciliopathies" have recently been diagnosed...
February 17, 2017: Cold Spring Harbor Perspectives in Biology
https://www.readbyqxmd.com/read/28202658/mechanisms-for-nonmitotic-activation-of-aurora-a-at-cilia
#5
REVIEW
Vladislav Korobeynikov, Alexander Y Deneka, Erica A Golemis
Overexpression of the Aurora kinase A (AURKA) is oncogenic in many tumors. Many studies of AURKA have focused on activities of this kinase in mitosis, and elucidated the mechanisms by which AURKA activity is induced at the G2/M boundary through interactions with proteins such as TPX2 and NEDD9. These studies have informed the development of small molecule inhibitors of AURKA, of which a number are currently under preclinical and clinical assessment. While the first activities defined for AURKA were its control of centrosomal maturation and organization of the mitotic spindle, an increasing number of studies over the past decade have recognized a separate biological function of AURKA, in controlling disassembly of the primary cilium, a small organelle protruding from the cell surface that serves as a signaling platform...
February 8, 2017: Biochemical Society Transactions
https://www.readbyqxmd.com/read/28174521/deep-sequencing-of-the-human-retinae-reveals-the-expression-of-odorant-receptors
#6
Nikolina Jovancevic, Kirsten A Wunderlich, Claudia Haering, Caroline Flegel, Désirée Maßberg, Markus Weinrich, Lea Weber, Lars Tebbe, Anselm Kampik, Günter Gisselmann, Uwe Wolfrum, Hanns Hatt, Lian Gelis
Several studies have demonstrated that the expression of odorant receptors (ORs) occurs in various tissues. These findings have served as a basis for functional studies that demonstrate the potential of ORs as drug targets for a clinical application. To the best of our knowledge, this report describes the first evaluation of the mRNA expression of ORs and the localization of OR proteins in the human retina that set a stage for subsequent functional analyses. RNA-Sequencing datasets of three individual neural retinae were generated using Next-generation sequencing and were compared to previously published but reanalyzed datasets of the peripheral and the macular human retina and to reference tissues...
2017: Frontiers in Cellular Neuroscience
https://www.readbyqxmd.com/read/28168444/fluid-shear-stress-induced-tgf-%C3%AE-alk5-signaling-in-renal-epithelial-cells-is-modulated-by-mek1-2
#7
Steven J Kunnen, Wouter N Leonhard, Cor Semeins, Lukas J A C Hawinkels, Christian Poelma, Peter Ten Dijke, Astrid Bakker, Beerend P Hierck, Dorien J M Peters
Renal tubular epithelial cells are exposed to mechanical forces due to fluid flow shear stress within the lumen of the nephron. These cells respond by activation of mechano-sensors located at the plasma membrane or the primary cilium, having crucial roles in maintenance of cellular homeostasis and signaling. In this paper, we applied fluid shear stress to study TGF-β signaling in renal epithelial cells with and without expression of the Pkd1-gene, encoding a mechano-sensor mutated in polycystic kidney disease...
February 6, 2017: Cellular and Molecular Life Sciences: CMLS
https://www.readbyqxmd.com/read/28158906/reduced-primary-cilia-length-and-altered-arl13b-expression-are-associated-with-deregulated-chondrocyte-hedgehog-signalling-in-alkaptonuria
#8
Stephen D Thorpe, Silvia Gambassi, Clare L Thompson, Charmilie Chandrakumar, Annalisa Santucci, Martin M Knight
Alkaptonuria (AKU) is a rare inherited disease resulting from a deficiency of the enzyme homogentisate 1,2-dioxygenase which leads to the accumulation of homogentisic acid (HGA). AKU is characterised by severe cartilage degeneration, similar to that observed in osteoarthritis. Previous studies suggest that AKU is associated with alterations in cytoskeletal organisation which could modulate primary cilia structure/function. This study investigated whether AKU is associated with changes in chondrocyte primary cilia and associated Hedgehog signalling which mediates cartilage degradation in osteoarthritis...
February 3, 2017: Journal of Cellular Physiology
https://www.readbyqxmd.com/read/28154525/deletion-of-type-3-adenylyl-cyclase-perturbs-the-postnatal-maturation-of-olfactory-sensory-neurons-and-olfactory-cilium-ultrastructure-in-mice
#9
Zhe Zhang, Dong Yang, Mengdi Zhang, Ning Zhu, Yanfen Zhou, Daniel R Storm, Zhenshan Wang
Type 3 adenylyl cyclase (Adcy3) is localized to the cilia of olfactory sensory neurons (OSNs) and is an essential component of the olfactory cyclic adenosine monophosphate (cAMP) signaling pathway. Although the role of this enzyme in odor detection and axonal projection in OSNs was previously characterized, researchers will still have to determine its function in the maturation of postnatal OSNs and olfactory cilium ultrastructure. Previous studies on newborns showed that the anatomic structure of the main olfactory epithelium (MOE) of Adcy3 knockout mice (Adcy3(-/-)) is indistinguishable from that of their wild-type littermates (Adcy3(+/+)), whereas the architecture and associated composition of MOE are relatively underdeveloped at this early age...
2017: Frontiers in Cellular Neuroscience
https://www.readbyqxmd.com/read/28154160/tubby-family-proteins-are-adapters-for-ciliary-trafficking-of-integral-membrane-proteins
#10
Hemant B Badgandi, Sun-Hee Hwang, Issei S Shimada, Evan Loriot, Saikat Mukhopadhyay
The primary cilium is a paradigmatic organelle for studying compartmentalized signaling; however, unlike soluble protein trafficking, processes targeting integral membrane proteins to cilia are poorly understood. In this study, we determine that the tubby family protein TULP3 functions as a general adapter for ciliary trafficking of structurally diverse integral membrane cargo, including multiple reported and novel rhodopsin family G protein-coupled receptors (GPCRs) and the polycystic kidney disease-causing polycystin 1/2 complex...
February 2, 2017: Journal of Cell Biology
https://www.readbyqxmd.com/read/28122914/localization-of-ndr2-to-peroxisomes-and-its-role-in-ciliogenesis
#11
Shoko Abe, Tomoaki Nagai, Moe Masukawa, Kanji Okumoto, Yuta Homma, Yukio Fujiki, Kensaku Mizuno
Nuclear Dbf2-related (NDR) kinases, comprising NDR1 and NDR2, are serine/threonine kinases that play crucial roles in the control of cell proliferation, apoptosis, and morphogenesis. We recently showed that NDR2, but not NDR1, is involved in primary cilium formation; however, the mechanism underlying their functional difference in ciliogenesis is unknown. To address this issue, we examined their subcellular localization. Despite their close sequence similarity, NDR2 exhibited punctate localization in the cytoplasm, whereas NDR1 was diffusely distributed within the cell...
January 25, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28122017/adenylate-cyclase-type-iii-is-not-a-ubiquitous-marker-for-all-primary-cilia-during-development
#12
Maria Cristina Antal, Karelle Bénardais, Brigitte Samama, Cyril Auger, Valérie Schini-Kerth, Said Ghandour, Nelly Boehm
Adenylate cyclase type III (AC3) is localized in plasma membrane of neuronal primary cilium and can be used as a marker of this cilium. AC3 has also been detected in some other primary cilia such as those of fibroblasts, synoviocytes or astrocytes. Despite the presence of a cilium in almost all cell types, we show that AC3 is not a common marker of all primary cilia of different human and mouse tissues during development. In peripheral organs, AC3 is present mainly in primary cilia in cells of the mesenchymal lineage (fibroblasts, chondroblasts, osteoblasts-osteocytes, odontoblasts, muscle cells and endothelial cells)...
2017: PloS One
https://www.readbyqxmd.com/read/28118669/the-ciliopathy-gene-ahi1-is-required-for-zebrafish-cone-photoreceptor-outer-segment-morphogenesis-and-survival
#13
Emma M Lessieur, Joseph Fogerty, Robert J Gaivin, Ping Song, Brian D Perkins
Purpose: Joubert syndrome (JBTS) is an autosomal recessive ciliopathy with considerable phenotypic variability. In addition to central nervous system abnormalities, a subset of JBTS patients exhibit retinal dystrophy and/or kidney disease. Mutations in the AHI1 gene are causative for approximately 10% of all JBTS cases. The purpose of this study was to generate ahi1 mutant alleles in zebrafish and to characterize the retinal phenotypes. Methods: Zebrafish ahi1 mutants were generated using transcription activator-like effector nucleases (TALENs)...
January 1, 2017: Investigative Ophthalmology & Visual Science
https://www.readbyqxmd.com/read/28114281/ubiquitination-and-regulation-of-aurka-identifies-a-hypoxia-independent-e3-ligase-activity-of-vhl
#14
E Hasanov, G Chen, P Chowdhury, J Weldon, Z Ding, E Jonasch, S Sen, C L Walker, R Dere
The hypoxia-regulated tumor-suppressor von Hippel-Lindau (VHL) is an E3 ligase that recognizes its substrates as part of an oxygen-dependent prolyl hydroxylase (PHD) reaction, with hypoxia-inducible factor α (HIFα) being its most notable substrate. Here we report that VHL has an equally important function distinct from its hypoxia-regulated activity. We find that Aurora kinase A (AURKA) is a novel, hypoxia-independent target for VHL ubiquitination. In contrast to its hypoxia-regulated activity, VHL mono-, rather than poly-ubiquitinates AURKA, in a PHD-independent reaction targeting AURKA for degradation in quiescent cells, where degradation of AURKA is required to maintain the primary cilium...
January 23, 2017: Oncogene
https://www.readbyqxmd.com/read/28108487/transition-zone-migration-a-mechanism-for-cytoplasmic-ciliogenesis-and-postaxonemal-centriole-elongation
#15
Tomer Avidor-Reiss, Andrew Ha, Marcus L Basiri
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...
January 20, 2017: Cold Spring Harbor Perspectives in Biology
https://www.readbyqxmd.com/read/28105929/a-compendium-of-human-genes-regulating-feeding-behavior-and-body-weight-its-functional-characterization-and-identification-of-gwas-genes-involved-in-brain-specific-ppi-network
#16
Elena V Ignatieva, Dmitry A Afonnikov, Olga V Saik, Evgeny I Rogaev, Nikolay A Kolchanov
BACKGROUND: Obesity is heritable. It predisposes to many diseases. The objectives of this study were to create a compendium of genes relevant to feeding behavior (FB) and/or body weight (BW) regulation; to construct and to analyze networks formed by associations between genes/proteins; and to identify the most significant genes, biological processes/pathways, and tissues/organs involved in BW regulation. RESULTS: The compendium of genes controlling FB or BW includes 578 human genes...
December 22, 2016: BMC Genetics
https://www.readbyqxmd.com/read/28100636/centriole-splitting-caused-by-loss-of-the-centrosomal-linker-protein-c-nap1-reduces-centriolar-satellite-density-and-impedes-centrosome-amplification
#17
Anne-Marie Flanagan, Elena Stavenschi, Shivakumar Basavaraju, David Gaboriau, David A Hoey, Ciaran G Morrison
Duplication of the centrosomes is a tightly regulated process. Abnormal centrosome numbers can impair cell division and cause changes in how cells migrate. Duplicated centrosomes are held together by a proteinaceous linker made up of rootletin filaments anchored to the centrioles by C-NAP1. This linker is removed in a NEK2A kinase-dependent manner as mitosis begins. To explore C-NAP1 activities in regulating centrosome activities, we used genome editing to ablate it. C-NAP1 null cells were viable and had an increased frequency of premature centriole separation, accompanied by reduced density of the centriolar satellites, with re-expression of C-NAP1 rescuing both these phenotypes...
January 18, 2017: Molecular Biology of the Cell
https://www.readbyqxmd.com/read/28089251/mutations-in-mapkbp1-cause-juvenile-or-late-onset-cilia-independent-nephronophthisis
#18
Maxence S Macia, Jan Halbritter, Marion Delous, Cecilie Bredrup, Arthur Gutter, Emilie Filhol, Anne E C Mellgren, Sabine Leh, Albane Bizet, Daniela A Braun, Heon Y Gee, Flora Silbermann, Charline Henry, Pauline Krug, Christine Bole-Feysot, Patrick Nitschké, Dominique Joly, Philippe Nicoud, André Paget, Heidi Haugland, Damien Brackmann, Nayir Ahmet, Richard Sandford, Nurcan Cengiz, Per M Knappskog, Helge Boman, Bolan Linghu, Fan Yang, Edward J Oakeley, Pierre Saint Mézard, Andreas W Sailer, Stefan Johansson, Eyvind Rødahl, Sophie Saunier, Friedhelm Hildebrandt, Alexandre Benmerah
Nephronophthisis (NPH), an autosomal-recessive tubulointerstitial nephritis, is the most common cause of hereditary end-stage renal disease in the first three decades of life. Since most NPH gene products (NPHP) function at the primary cilium, NPH is classified as a ciliopathy. We identified mutations in a candidate gene in eight individuals from five families presenting late-onset NPH with massive renal fibrosis. This gene encodes MAPKBP1, a poorly characterized scaffolding protein for JNK signaling. Immunofluorescence analyses showed that MAPKBP1 is not present at the primary cilium and that fibroblasts from affected individuals did not display ciliogenesis defects, indicating that MAPKBP1 may represent a new family of NPHP not involved in cilia-associated functions...
February 2, 2017: American Journal of Human Genetics
https://www.readbyqxmd.com/read/28069795/intraflagellar-transport-88-ift88-is-crucial-for-craniofacial-development-in-mice-and-is-a-candidate-gene-for-human-cleft-lip-and-palate
#19
Hua Tian, Jifan Feng, Jingyuan Li, Thach-Vu Ho, Yuan Yuan, Yang Liu, Frederick Brindopke, Jane C Figueiredo, William Magee, Pedro A Sanchez-Lara, Yang Chai
Ciliopathies are pleiotropic human diseases resulting from defects of the primary cilium, and these patients often have cleft lip and palate. IFT88 is required for the assembly and function of the primary cilia, which mediate the activity of key developmental signaling pathways. Through whole exome sequencing of a family of three affected siblings with isolated cleft lip and palate, we discovered that they share a novel missense mutation in IFT88 (c.915G>C, p.E305D), suggesting this gene should be considered a candidate for isolated orofacial clefting...
January 9, 2017: Human Molecular Genetics
https://www.readbyqxmd.com/read/28062565/the-biology-of-ciliary-dynamics
#20
Kuo-Shun Hsu, Jen-Zen Chuang, Ching-Hwa Sung
The cilium is an evolutionally conserved apical membrane protrusion that senses and transduces diverse signals to regulate a wide range of cellular activities. The cilium is dynamic in length, structure, and protein composition. Dysregulation of ciliary dynamics has been linked with ciliopathies and other human diseases. The cilium undergoes cell-cycle-dependent assembly and disassembly, with ciliary resorption linked with G1-S transition and cell-fate choice. In the resting cell, the cilium remains sensitive to environmental cues for remodeling during tissue homeostasis and repair...
January 6, 2017: Cold Spring Harbor Perspectives in Biology
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