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https://read.qxmd.com/read/30745319/nuclear-import-of-the-dscam-cytoplasmic-domain-drives-signaling-capable-of-inhibiting-synapse-formation
#1
Sonja M Sachse, Sam Lievens, Luís F Ribeiro, Dan Dascenco, Delphine Masschaele, Katrien Horré, Anke Misbaer, Nele Vanderroost, Anne Sophie De Smet, Evgenia Salta, Maria-Luise Erfurth, Yoshiaki Kise, Siegfried Nebel, Wouter Van Delm, Stéphane Plaisance, Jan Tavernier, Bart De Strooper, Joris De Wit, Dietmar Schmucker
DSCAM and DSCAML1 are immunoglobulin and cell adhesion-type receptors serving important neurodevelopmental functions including control of axon growth, branching, neurite self-avoidance, and neuronal cell death. The signal transduction mechanisms or effectors of DSCAM receptors, however, remain poorly characterized. We used a human ORFeome library to perform a high-throughput screen in mammalian cells and identified novel cytoplasmic signaling effector candidates including the Down syndrome kinase Dyrk1a, STAT3, USP21, and SH2D2A...
February 11, 2019: EMBO Journal
https://read.qxmd.com/read/30737259/length-independent-telomere-damage-drives-post-mitotic-cardiomyocyte-senescence
#2
Rhys Anderson, Anthony Lagnado, Damien Maggiorani, Anna Walaszczyk, Emily Dookun, James Chapman, Jodie Birch, Hanna Salmonowicz, Mikolaj Ogrodnik, Diana Jurk, Carole Proctor, Clara Correia-Melo, Stella Victorelli, Edward Fielder, Rolando Berlinguer-Palmini, Andrew Owens, Laura C Greaves, Kathy L Kolsky, Angelo Parini, Victorine Douin-Echinard, Nathan K LeBrasseur, Helen M Arthur, Simon Tual-Chalot, Marissa J Schafer, Carolyn M Roos, Jordan D Miller, Neil Robertson, Jelena Mann, Peter D Adams, Tamara Tchkonia, James L Kirkland, Jeanne Mialet-Perez, Gavin D Richardson, João F Passos
Ageing is the biggest risk factor for cardiovascular disease. Cellular senescence, a process driven in part by telomere shortening, has been implicated in age-related tissue dysfunction. Here, we address the question of how senescence is induced in rarely dividing/post-mitotic cardiomyocytes and investigate whether clearance of senescent cells attenuates age-related cardiac dysfunction. During ageing, human and murine cardiomyocytes acquire a senescent-like phenotype characterised by persistent DNA damage at telomere regions that can be driven by mitochondrial dysfunction and crucially can occur independently of cell division and telomere length...
February 8, 2019: EMBO Journal
https://read.qxmd.com/read/30737258/defining-multistep-cell-fate-decision-pathways-during-pancreatic-development-at-single-cell-resolution
#3
Xin-Xin Yu, Wei-Lin Qiu, Liu Yang, Yu Zhang, Mao-Yang He, Lin-Chen Li, Cheng-Ran Xu
The generation of terminally differentiated cell lineages during organogenesis requires multiple, coordinated cell fate choice steps. However, this process has not been clearly delineated, especially in complex solid organs such as the pancreas. Here, we performed single-cell RNA-sequencing in pancreatic cells sorted from multiple genetically modified reporter mouse strains at embryonic stages E9.5-E17.5. We deciphered the developmental trajectories and regulatory strategies of the exocrine and endocrine pancreatic lineages as well as intermediate progenitor populations along the developmental pathways...
February 8, 2019: EMBO Journal
https://read.qxmd.com/read/30733243/endophilin-a-regulates-presynaptic-ca-2-influx-and-synaptic-vesicle-recycling-in-auditory-hair-cells
#4
Jana Kroll, Lina M Jaime Tobón, Christian Vogl, Jakob Neef, Ilona Kondratiuk, Melanie König, Nicola Strenzke, Carolin Wichmann, Ira Milosevic, Tobias Moser
Ribbon synapses of cochlear inner hair cells (IHCs) operate with high rates of neurotransmission; yet, the molecular regulation of synaptic vesicle (SV) recycling at these synapses remains poorly understood. Here, we studied the role of endophilins-A1-3, endocytic adaptors with curvature-sensing and curvature-generating properties, in mouse IHCs. Single-cell RT-PCR indicated the expression of endophilins-A1-3 in IHCs, and immunoblotting confirmed the presence of endophilin-A1 and endophilin-A2 in the cochlea...
February 7, 2019: EMBO Journal
https://read.qxmd.com/read/30733242/cas9-slide-and-seek-for-phage-defense-and-genome-engineering
#5
Andrew Santiago-Frangos, Tanner Wiegand, Blake Wiedenheft
No abstract text is available yet for this article.
February 7, 2019: EMBO Journal
https://read.qxmd.com/read/30723117/ezh2-cooperates-with-gain-of-function-p53-mutants-to-promote-cancer-growth-and-metastasis
#6
Yu Zhao, Liya Ding, Dejie Wang, Zhenqing Ye, Yundong He, Linlin Ma, Runzhi Zhu, Yunqian Pan, Qiang Wu, Kun Pang, Xiaonan Hou, Saravut J Weroha, Conghui Han, Roger Coleman, Ilsa Coleman, R Jeffery Karnes, Jun Zhang, Peter S Nelson, Liguo Wang, Haojie Huang
In light of the increasing number of identified cancer-driven gain-of-function (GOF) mutants of p53, it is important to define a common mechanism to systematically target several mutants, rather than developing strategies tailored to inhibit each mutant individually. Here, using RNA immunoprecipitation-sequencing (RIP-seq), we identified the Polycomb-group histone methyltransferase EZH2 as a p53 mRNA-binding protein. EZH2 bound to an internal ribosome entry site (IRES) in the 5'UTR of p53 mRNA and enhanced p53 protein translation in a methyltransferase-independent manner...
February 5, 2019: EMBO Journal
https://read.qxmd.com/read/30718273/an-airway-organoid-is-forever
#7
Margherita Paschini, Carla F Kim
No abstract text is available yet for this article.
February 4, 2019: EMBO Journal
https://read.qxmd.com/read/30696688/the-herpesviral-antagonist-m152-reveals-differential-activation-of-sting-dependent-irf-and-nf-%C3%AE%C2%BAb-signaling-and-sting-s-dual-role-during-mcmv-infection
#8
Markus Stempel, Baca Chan, Vanda Juranić Lisnić, Astrid Krmpotić, Josephine Hartung, Søren R Paludan, Nadia Füllbrunn, Niels Aw Lemmermann, Melanie M Brinkmann
Cytomegaloviruses (CMVs) are master manipulators of the host immune response. Here, we reveal that the murine CMV (MCMV) protein m152 specifically targets the type I interferon (IFN) response by binding to stimulator of interferon genes (STING), thereby delaying its trafficking to the Golgi compartment from where STING initiates type I IFN signaling. Infection with an MCMV lacking m152 induced elevated type I IFN responses and this leads to reduced viral transcript levels both in vitro and in vivo This effect is ameliorated in the absence of STING Interestingly, while m152 inhibits STING-mediated IRF signaling, it did not affect STING-mediated NF-κB signaling...
January 29, 2019: EMBO Journal
https://read.qxmd.com/read/30692134/abnormal-tdp-43-function-impairs-activity-dependent-bdnf-secretion-synaptic-plasticity-and-cognitive-behavior-through-altered-sortilin-splicing
#9
Jason Y Tann, Lik-Wei Wong, Sreedharan Sajikumar, Carlos F Ibáñez
Aberrant function of the RNA-binding protein TDP-43 has been causally linked to multiple neurodegenerative diseases. Due to its large number of targets, the mechanisms through which TDP-43 malfunction cause disease are unclear. Here, we report that knockdown, aggregation, or disease-associated mutation of TDP-43 all impair intracellular sorting and activity-dependent secretion of the neurotrophin brain-derived neurotrophic factor (BDNF) through altered splicing of the trafficking receptor Sortilin. Adult mice lacking TDP-43 specifically in hippocampal CA1 show memory impairment and synaptic plasticity defects that can be rescued by restoring Sortilin splicing or extracellular BDNF...
January 28, 2019: EMBO Journal
https://read.qxmd.com/read/30692133/the-pseudokinase-trib1-toggles-an-intramolecular-switch-to-regulate-cop1-nuclear-export
#10
Jennifer E Kung, Natalia Jura
COP1 is a highly conserved ubiquitin ligase that regulates diverse cellular processes in plants and metazoans. Tribbles pseudokinases, which only exist in metazoans, act as scaffolds that interact with COP1 and its substrates to facilitate ubiquitination. Here, we report that, in addition to this scaffolding role, TRIB1 promotes nuclear localization of COP1 by disrupting an intramolecular interaction between the WD40 domain and a previously uncharacterized regulatory site within COP1. This site, which we have termed the pseudosubstrate latch (PSL), resembles the consensus COP1-binding motif present in known COP1 substrates...
January 28, 2019: EMBO Journal
https://read.qxmd.com/read/30679198/getting-into-shape-tissue-tension-drives-oriented-cell-divisions-during-organogenesis
#11
Lathiena A Manning, Mark Peifer
No abstract text is available yet for this article.
January 24, 2019: EMBO Journal
https://read.qxmd.com/read/30679197/nonsense-shielding-protecting-rna-from-decay-leads-to-cancer
#12
Miles F Wilkinson, Heidi Cook-Andersen
No abstract text is available yet for this article.
January 24, 2019: EMBO Journal
https://read.qxmd.com/read/30643021/long-term-expanding-human-airway-organoids-for-disease-modeling
#13
Norman Sachs, Angelos Papaspyropoulos, Domenique D Zomer-van Ommen, Inha Heo, Lena Böttinger, Dymph Klay, Fleur Weeber, Guizela Huelsz-Prince, Nino Iakobachvili, Gimano D Amatngalim, Joep de Ligt, Arne van Hoeck, Natalie Proost, Marco C Viveen, Anna Lyubimova, Luc Teeven, Sepideh Derakhshan, Jeroen Korving, Harry Begthel, Johanna F Dekkers, Kuldeep Kumawat, Emilio Ramos, Matthijs Fm van Oosterhout, G Johan Offerhaus, Dominique J Wiener, Eduardo P Olimpio, Krijn K Dijkstra, Egbert F Smit, Maarten van der Linden, Sridevi Jaksani, Marieke van de Ven, Jos Jonkers, Anne C Rios, Emile E Voest, Coline Hm van Moorsel, Cornelis K van der Ent, Edwin Cuppen, Alexander van Oudenaarden, Frank E Coenjaerts, Linde Meyaard, Louis J Bont, Peter J Peters, Sander J Tans, Jeroen S van Zon, Sylvia F Boj, Robert G Vries, Jeffrey M Beekman, Hans Clevers
Organoids are self-organizing 3D structures grown from stem cells that recapitulate essential aspects of organ structure and function. Here, we describe a method to establish long-term-expanding human airway organoids from broncho-alveolar resections or lavage material. The pseudostratified airway organoids consist of basal cells, functional multi-ciliated cells, mucus-producing secretory cells, and CC10-secreting club cells. Airway organoids derived from cystic fibrosis (CF) patients allow assessment of CFTR function in an organoid swelling assay...
January 14, 2019: EMBO Journal
https://read.qxmd.com/read/30643020/revealing-the-superpowers-of-primpol-rescuing-replicating-microsatellites
#14
Jane Ea Reid, Tamás Fischer
No abstract text is available yet for this article.
January 14, 2019: EMBO Journal
https://read.qxmd.com/read/30643019/bacterial-killing-by-complement-requires-membrane-attack-complex-formation-via-surface-bound-c5-convertases
#15
Dani Ac Heesterbeek, Bart W Bardoel, Edward S Parsons, Isabel Bennett, Maartje Ruyken, Dennis J Doorduijn, Ronald D Gorham, Evelien Tm Berends, Alice Lb Pyne, Bart W Hoogenboom, Suzan Hm Rooijakkers
The immune system kills bacteria by the formation of lytic membrane attack complexes (MACs), triggered when complement enzymes cleave C5. At present, it is not understood how the MAC perturbs the composite cell envelope of Gram-negative bacteria. Here, we show that the role of C5 convertase enzymes in MAC assembly extends beyond the cleavage of C5 into the MAC precursor C5b. Although purified MAC complexes generated from preassembled C5b6 perforate artificial lipid membranes and mammalian cells, these components lack bactericidal activity...
January 14, 2019: EMBO Journal
https://read.qxmd.com/read/30643018/an-increase-in-neural-stem-cells-and-olfactory-bulb-adult-neurogenesis-improves-discrimination-of-highly-similar-odorants
#16
Sara Bragado Alonso, Janine K Reinert, Nicolas Marichal, Simone Massalini, Benedikt Berninger, Thomas Kuner, Federico Calegari
Adult neurogenesis is involved in cognitive performance but studies that manipulated this process to improve brain function are scarce. Here, we characterized a genetic mouse model in which neural stem cells (NSC) of the subventricular zone (SVZ) were temporarily expanded by conditional expression of the cell cycle regulators Cdk4/cyclinD1, thus increasing neurogenesis. We found that supernumerary neurons matured and integrated in the olfactory bulb similarly to physiologically generated newborn neurons displaying a correct expression of molecular markers, morphology and electrophysiological activity...
January 14, 2019: EMBO Journal
https://read.qxmd.com/read/30635335/localized-incorporation-of-outer-membrane-components-in-the-pathogen-brucella-abortus
#17
Victoria Vassen, Claire Valotteau, Cécile Feuillie, Cécile Formosa-Dague, Yves F Dufrêne, Xavier De Bolle
The zoonotic pathogen Brucella abortus is part of the Rhizobiales, which are alpha-proteobacteria displaying unipolar growth. Here, we show that this bacterium exhibits heterogeneity in its outer membrane composition, with clusters of rough lipopolysaccharide co-localizing with the essential outer membrane porin Omp2b, which is proposed to allow facilitated diffusion of solutes through the porin. We also show that the major outer membrane protein Omp25 and peptidoglycan are incorporated at the new pole and the division site, the expected growth sites...
January 11, 2019: EMBO Journal
https://read.qxmd.com/read/30635334/atoh1-secretory-progenitors-possess-renewal-capacity-independent-of-lgr5-cells-during-colonic-regeneration
#18
David Castillo-Azofeifa, Elena N Fazio, Roy Nattiv, Hayley J Good, Tomas Wald, Michael A Pest, Frederic J de Sauvage, Ophir D Klein, Samuel Asfaha
During homeostasis, the colonic epithelium is replenished every 3-5 days by rapidly cycling Lgr5 + stem cells. However, various insults can lead to depletion of Lgr5 + stem cells, and colonic epithelium can be regenerated from Lgr5- negative cells. While studies in the small intestine have addressed the lineage identity of the Lgr5- negative regenerative cell population, in the colon this question has remained unanswered. Here, we set out to identify which cell(s) contribute to colonic regeneration by performing genetic fate-mapping studies of progenitor populations in mice...
January 11, 2019: EMBO Journal
https://read.qxmd.com/read/30635333/transcriptional-regulation-of-normal-human-mammary-cell-heterogeneity-and-its-perturbation-in-breast-cancer
#19
REVIEW
Davide Pellacani, Susanna Tan, Sylvain Lefort, Connie J Eaves
The mammary gland in adult women consists of biologically distinct cell types that differ in their surface phenotypes. Isolation and molecular characterization of these subpopulations of mammary cells have provided extensive insights into their different transcriptional programs and regulation. This information is now serving as a baseline for interpreting the heterogeneous features of human breast cancers. Examination of breast cancer mutational profiles further indicates that most have undergone a complex evolutionary process even before being detected...
January 11, 2019: EMBO Journal
https://read.qxmd.com/read/30630857/clustering-of-tau-fibrils-impairs-the-synaptic-composition-of-%C3%AE-3-na-k-atpase-and-ampa-receptors
#20
Amulya Nidhi Shrivastava, Virginie Redeker, Laura Pieri, Luc Bousset, Marianne Renner, Karine Madiona, Caroline Mailhes-Hamon, Audrey Coens, Luc Buée, Philippe Hantraye, Antoine Triller, Ronald Melki
Tau assemblies have prion-like properties: they propagate from one neuron to another and amplify by seeding the aggregation of endogenous Tau. Although key in prion-like propagation, the binding of exogenous Tau assemblies to the plasma membrane of naïve neurons is not understood. We report that fibrillar Tau forms clusters at the plasma membrane following lateral diffusion. We found that the fibrils interact with the Na+ /K+ -ATPase (NKA) and AMPA receptors. The consequence of the clustering is a reduction in the amount of α3-NKA and an increase in the amount of GluA2-AMPA receptor at synapses...
January 10, 2019: EMBO Journal
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