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Corinne Stoetzel, Séverine Bär, Johan-Owen De Craene, Sophie Scheidecker, Christelle Etard, Johana Chicher, Jennifer R Reck, Isabelle Perrault, Véronique Geoffroy, Kirsley Chennen, Uwe Strähle, Philippe Hammann, Sylvie Friant, Hélène Dollfus
Ciliopathies are a group of diseases that affect kidney and retina among other organs. Here, we identify a missense mutation in PIK3R4 (phosphoinositide 3-kinase regulatory subunit 4, named VPS15) in a family with a ciliopathy phenotype. Besides being required for trafficking and autophagy, we show that VPS15 regulates primary cilium length in human fibroblasts, as well as ciliary processes in zebrafish. Furthermore, we demonstrate its interaction with the golgin GM130 and its localization to the Golgi. The VPS15-R998Q patient mutation impairs Golgi trafficking functions in humanized yeast cells...
November 24, 2016: Nature Communications
Zhengang Zhang, Wei Li, Yong Zhang, Ling Zhang, Maria E Teves, Hong Liu, Jerome F Strauss, Gregory J Pazour, James A Foster, Rex A Hess, Zhibing Zhang
Intraflagellar transport (IFT) is a conserved mechanism thought to be essential for the assembly and maintenance of cilia and flagella. However, little is known about its role in mammalian sperm flagella formation. To fill this gap, we disrupted the Ift20 gene in male germ cells. Homozygous mutant mice were infertile with significantly reduced sperm counts and motility. In addition, abnormally shaped elongating spermatid heads and bulbous round spermatids were found in the lumen of the seminiferous tubules...
September 28, 2016: Molecular Biology of the Cell
Soyoung Rhee, Gregory W Kirschen, Yan Gu, Shaoyu Ge
The primary cilium, a sensory organelle, regulates cell proliferation and neuronal development of dentate granule cells in the hippocampus. However, its role in the function of mature dentate granule cells remains unknown. Here we specifically depleted and disrupted ciliary proteins IFT20 and Kif3A (respectively) in mature dentate granule cells and investigated hippocampus-dependent contextual memory and long-term plasticity at mossy fiber synapses. We found that depletion of IFT20 in these cells significantly impaired context-dependent fear-related memory...
September 28, 2016: Scientific Reports
Kazuo Noda, Megumi Kitami, Kohei Kitami, Masaru Kaku, Yoshihiro Komatsu
The primary cilium is a cellular organelle that coordinates signaling pathways critical for cell proliferation, differentiation, survival, and homeostasis. Intraflagellar transport (IFT) plays a pivotal role in assembling primary cilia. Disruption and/or dysfunction of IFT components can cause multiple diseases, including skeletal dysplasia. However, the mechanism by which IFT regulates skeletogenesis remains elusive. Here, we show that a neural crest-specific deletion of intraflagellar transport 20 (Ift20) in mice compromises ciliogenesis and intracellular transport of collagen, which leads to osteopenia in the facial region...
May 10, 2016: Proceedings of the National Academy of Sciences of the United States of America
Omar I Vivar, Giulia Masi, Jean-Marie Carpier, Joao G Magalhaes, Donatella Galgano, Gregory J Pazour, Sebastian Amigorena, Claire Hivroz, Cosima T Baldari
Biogenesis of the immune synapse at the interface between antigen-presenting cells and T cells assembles and organizes a large number of membrane proteins required for effective signaling through the T-cell receptor. We showed previously that the intraflagellar transport protein 20 (IFT20), a component of the intraflagellar transport system, controls polarized traffic during immune synapse assembly. To investigate the role of IFT20 in primary CD4(+) T cells in vitro and in vivo, we generated mice bearing a conditional defect of IFT20 expression in T cells...
January 12, 2016: Proceedings of the National Academy of Sciences of the United States of America
Saul S Siller, Michael C Burke, Feng-Qian Li, Ken-Ichi Takemaru
Airway cilia provide the coordinated motive force for mucociliary transport, which prevents the accumulation of mucus, debris, pollutants, and bacteria in our respiratory tracts. As airway cilia are constantly exposed to the environment and, hence, are an integral component of the pathogenesis of several congenital and chronic pulmonary disorders, it is necessary to understand the molecular mechanisms that control ciliated cell differentiation and ciliogenesis. We have previously reported that loss of the basal body protein Chibby (Cby) results in chronic upper airway infection in mice due to a significant reduction in the number of airway cilia...
2015: Cell Cycle
Liangliang He, Wenyan Xu, Ying Jing, Ming Wu, Shuwei Song, Ying Cao, Changlin Mei
The Hippo signaling pathway and its transcriptional co-activator Yap are known as essential regulators for cell proliferation and organ size. However, little is known about their roles in kidney development and ciliogenesis. We examined expression of Yap during zebrafish embryogenesis, and its transcripts were detected in pronephric duct, while Yap protein was found to be localized in the cytoplasm and apical membrane in kidney epithelium cells. By morpholino (MO) knockdown of yap expression in zebrafish, the injected larve exhibits pronephic cysts and many aspects of ciliopathy, which can be rescued by full-length yap mRNA, but not yap (S127A) mRNA...
2015: International Journal of Biological Sciences
Xue Yuan, Lee Ann Garrett-Sinha, Debanjan Sarkar, Shuying Yang
IFT20 is the smallest member of the intraflagellar transport protein (IFT) complex B. It is involved in cilia formation. Studies of IFT20 have been confined to ciliated cells. Recently, IFT20 was found to be also expressed in non-ciliated T cells and have functions in immune synapse formation and signaling in vitro. However, how IFT20 regulates T-cell development and activation in vivo is still unknown. We deleted the IFT20 gene in early and later stages of T-cell development by crossing IFT20(flox/flox) (IFT20(f/f) ) mice with Lck-Cre and CD4-Cre transgenic mice, and investigated the role of IFT20 in T-cell maturation and in the development of T cell-mediated collagen-induced arthritis (CIA)...
2014: Bone Research
Francesca Finetti, Laura Patrussi, Donatella Galgano, Chiara Cassioli, Giuseppe Perinetti, Gregory J Pazour, Cosima T Baldari
IFT20, a component of the intraflagellar transport (IFT) system that controls ciliogenesis, regulates immune synapse assembly in the non-ciliated T-cell by promoting T-cell receptor (TCR) recycling. Here, we have addressed the role of Rab8 (for which there are two isoforms Rab8a and Rab8b), a small GTPase implicated in ciliogenesis, in TCR traffic to the immune synapse. We show that Rab8, which colocalizes with IFT20 in Rab11(+) endosomes, is required for TCR recycling. Interestingly, as opposed to in IFT20-deficient T-cells, TCR(+) endosomes polarized normally beneath the immune synapse membrane in the presence of dominant-negative Rab8, but were unable to undergo the final docking or fusion step...
July 15, 2015: Journal of Cell Science
A Onnis, F Finetti, L Patrussi, M Gottardo, C Cassioli, S Spanò, C T Baldari
Accumulating evidence underscores the T-cell immune synapse (IS) as a site of intense vesicular trafficking, on which productive signaling and cell activation crucially depend. Although the T-cell antigen receptor (TCR) is known to exploit recycling to accumulate to the IS, the specific pathway that controls this process remains to be elucidated. Here we demonstrate that the small GTPase Rab29 is centrally implicated in TCR trafficking and IS assembly. Rab29 colocalized and interacted with Rab8, Rab11 and IFT20, a component of the intraflagellar transport system that regulates ciliogenesis and participates in TCR recycling in the non-ciliated T cell, as assessed by co-immunoprecipitation and immunofluorescence analysis...
October 2015: Cell Death and Differentiation
Elena Reales, Miguel Bernabé-Rubio, Javier Casares-Arias, Carles Rentero, Jaime Fernández-Barrera, Laura Rangel, Isabel Correas, Carlos Enrich, Germán Andrés, Miguel A Alonso
The base of the primary cilium contains a zone of condensed membranes whose importance is not known. Here, we have studied the involvement of MAL, a tetraspanning protein that exclusively partitions into condensed membrane fractions, in the condensation of membranes at the ciliary base and investigated the importance of these membranes in primary cilium formation. We show that MAL accumulates at the ciliary base of epithelial MDCK cells. Knockdown of MAL expression resulted in a drastic reduction in the condensation of membranes at the ciliary base, the percentage of ciliated cells and the length of the cilia, but did not affect the docking of the centrosome to the plasma membrane or produce missorting of proteins to the pericentriolar zone or to the membrane of the remaining cilia...
June 15, 2015: Journal of Cell Science
Quanlong Lu, Christine Insinna, Carolyn Ott, Jimmy Stauffer, Petra A Pintado, Juliati Rahajeng, Ulrich Baxa, Vijay Walia, Adrian Cuenca, Yoo-Seok Hwang, Ira O Daar, Susana Lopes, Jennifer Lippincott-Schwartz, Peter K Jackson, Steve Caplan, Christopher J Westlake
Membrane association with mother centriole (M-centriole) distal appendages is critical for ciliogenesis initiation. How the Rab GTPase Rab11-Rab8 cascade functions in early ciliary membrane assembly is unknown. Here, we show that the membrane shaping proteins EHD1 and EHD3, in association with the Rab11-Rab8 cascade, function in early ciliogenesis. EHD1 and EHD3 localize to preciliary membranes and the ciliary pocket. EHD-dependent membrane tubulation is essential for ciliary vesicle formation from smaller distal appendage vesicles (DAVs)...
March 2015: Nature Cell Biology
Helen L May-Simera, Ronald S Petralia, Mireille Montcouquiol, Ya-Xian Wang, Katherine B Szarama, Yun Liu, Weichun Lin, Michael R Deans, Gregory J Pazour, Matthew W Kelley
Primary cilia have been implicated in the generation of planar cell polarity (PCP). However, variations in the severity of polarity defects in different cilia mutants, coupled with recent demonstrations of non-cilia-related actions of some cilia genes, make it difficult to determine the basis of these polarity defects. To address this issue, we evaluated PCP defects in cochlea from a selection of mice with mutations in cilia-related genes. Results indicated notable PCP defects, including mis-oriented hair cell stereociliary bundles, in Bbs8 and Ift20 single mutants that are more severe than in other cilia gene knockouts...
February 1, 2015: Development
Silene Ferraro, Ana I Gomez-Montalvo, Ruth Olmos, Monica Ramirez, Monica Lamas
Primary cilia are specialized organelles that extend from the cell surface and concentrate signal transduction components. In the nervous system, primary cilia-associated signals, such as sonic hedgehog (Shh), regulate cell proliferation and neuronal fate. Primary cilia assembly and maintenance require a multi-subunit intraflagellar transport (IFT) protein complex. Defects in primary cilia and IFT proteins are associated to severe pathological phenotypes. In the retina, the study of primary cilia has been mainly restricted to the specialized photoreceptor outer segment...
May 2015: Cellular and Molecular Neurobiology
Nele Schwarz, Amanda-Jayne Carr, Amelia Lane, Fabian Moeller, Li Li Chen, Mònica Aguilà, Britta Nommiste, Manickam N Muthiah, Naheed Kanuga, Uwe Wolfrum, Kerstin Nagel-Wolfrum, Lyndon da Cruz, Peter J Coffey, Michael E Cheetham, Alison J Hardcastle
Mutations in the RP2 gene lead to a severe form of X-linked retinitis pigmentosa. RP2 patients frequently present with nonsense mutations and no treatments are currently available to restore RP2 function. In this study, we reprogrammed fibroblasts from an RP2 patient carrying the nonsense mutation c.519C>T (p.R120X) into induced pluripotent stem cells (iPSC), and differentiated these cells into retinal pigment epithelial cells (RPE) to study the mechanisms of disease and test potential therapies. RP2 protein was undetectable in the RP2 R120X patient cells, suggesting a disease mechanism caused by complete lack of RP2 protein...
February 15, 2015: Human Molecular Genetics
Joost R Broekhuis, Kristen J Verhey, Gert Jansen
Primary cilia are important sensory organelles. They exist in a wide variety of lengths, which could reflect different cell-specific functions. How cilium length is regulated is unclear, but it probably involves intraflagellar transport (IFT), which transports protein complexes along the ciliary axoneme. Studies in various organisms have identified the small, conserved family of ros-cross hybridizing kinases (RCK) as regulators of cilium length. Here we show that Intestinal Cell Kinase (ICK) and MAPK/MAK/MRK overlapping kinase (MOK), two members of this family, localize to cilia of mouse renal epithelial (IMCD-3) cells and negatively regulate cilium length...
2014: PloS One
Chanjae Lee, John B Wallingford, Jeffrey M Gross
PURPOSE: To identify the mutation and cell biological underpinnings of photoreceptor defects in zebrafish au5 mutants. METHODS: Whole genome sequencing and SNP mapping were used to determine the genomic interval that harbors the au5 mutation. A candidate mutation was cloned and sequenced, and mRNA rescue used to validate that the affected gene was correctly identified. In situ hybridization, immunohistochemistry, and confocal imaging were used to determine the effects on photoreceptor development and maintenance in mutant retinae, and to determine if ciliogenesis or cilia-dependent development was affected in mutant embryos...
July 2014: Investigative Ophthalmology & Visual Science
Jacquelin A Crouse, Vanda S Lopes, Jovenal T Sanagustin, Brian T Keady, David S Williams, Gregory J Pazour
In the vertebrate retina, light is detected by the outer segments of photoreceptor rods and cones, which are highly modified cilia. Like other cilia, outer segments have no protein synthetic capacity and depend on proteins made in the cell body for their formation and maintenance. The mechanism of transport into the outer segment is not fully understood but intraflagellar transport (IFT) is thought to be a major mechanism for moving protein from the cell body into the cilium. In the case of photoreceptor cells, the high density of receptors and the disk turnover that occurs daily necessitates much higher rates of transport than would be required in other cilia...
May 2014: Cytoskeleton
Francesca Finetti, Laura Patrussi, Giulia Masi, Anna Onnis, Donatella Galgano, Orso Maria Lucherini, Gregory J Pazour, Cosima T Baldari
T cell activation requires sustained signaling at the immune synapse, a specialized interface with the antigen-presenting cell (APC) that assembles following T cell antigen receptor (TCR) engagement by major histocompatibility complex (MHC)-bound peptide. Central to sustained signaling is the continuous recruitment of TCRs to the immune synapse. These TCRs are partly mobilized from an endosomal pool by polarized recycling. We have identified IFT20, a component of the intraflagellar transport (IFT) system that controls ciliogenesis, as a central regulator of TCR recycling to the immune synapse...
May 1, 2014: Journal of Cell Science
Kwangsic Joo, Chang Gun Kim, Mi-Sun Lee, Hyun-Yi Moon, Sang-Hee Lee, Mi Jeong Kim, Hee-Seok Kweon, Woong-Yang Park, Cheol-Hee Kim, Joseph G Gleeson, Joon Kim
The initiation of primary cilium assembly entails the docking of ciliary vesicles presumably derived from the Golgi complex to the distal end of the mother centriole. Distal appendages, which anchor the mother centriole to the plasma membrane, are thought to be involved in the docking process. However, little is known about the molecular players and mechanisms that mediate the vesicle-centriole association. Here we report that coiled-coil domain containing 41 (CCDC41) is required for the docking of ciliary vesicles...
April 9, 2013: Proceedings of the National Academy of Sciences of the United States of America
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