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Cell Reports

Amy E Vincent, Kathryn White, Tracey Davey, Jonathan Philips, R Todd Ogden, Conor Lawess, Charlotte Warren, Matt G Hall, Yi Shiau Ng, Gavin Falkous, Thomas Holden, David Deehan, Robert W Taylor, Doug M Turnbull, Martin Picard
Genetic and biochemical defects of mitochondrial function are a major cause of human disease, but their link to mitochondrial morphology in situ has not been defined. Here, we develop a quantitative three-dimensional approach to map mitochondrial network organization in human muscle at electron microscopy resolution. We establish morphological differences between human and mouse and among patients with mitochondrial DNA (mtDNA) diseases compared to healthy controls. We also define the ultrastructure and prevalence of mitochondrial nanotunnels, which exist as either free-ended or connecting membrane protrusions across non-adjacent mitochondria...
January 14, 2019: Cell Reports
Chiu-An Lo, Ibrahim Kays, Farida Emran, Tsung-Jung Lin, Vedrana Cvetkovska, Brian Edwin Chen
No abstract text is available yet for this article.
March 12, 2019: Cell Reports
Paul T Ranum, Alexander T Goodwin, Hidekane Yoshimura, Diana L Kolbe, William D Walls, Jin-Young Koh, David Z Z He, Richard J H Smith
Single-cell RNA sequencing is a powerful tool by which to characterize the transcriptional profile of low-abundance cell types, but its application to the inner ear has been hampered by the bony labyrinth, tissue sparsity, and difficulty dissociating the ultra-rare cells of the membranous cochlea. Herein, we present a method to isolate individual inner hair cells (IHCs), outer hair cells (OHCs), and Deiters' cells (DCs) from the murine cochlea at any post-natal time point. We harvested more than 200 murine IHCs, OHCs, and DCs from post-natal days 15 (p15) to 228 (p228) and leveraged both short- and long-read single-cell RNA sequencing to profile transcript abundance and structure...
March 12, 2019: Cell Reports
Xiaojun Wang, Jason Tucciarone, Siqi Jiang, Fangfang Yin, Bor-Shuen Wang, Dingkang Wang, Yao Jia, Xueyan Jia, Yuxin Li, Tao Yang, Zhengchao Xu, Masood A Akram, Yusu Wang, Shaoqun Zeng, Giorgio A Ascoli, Partha Mitra, Hui Gong, Qingming Luo, Z Josh Huang
Parsing diverse nerve cells into biological types is necessary for understanding neural circuit organization. Morphology is an intuitive criterion for neuronal classification and a proxy of connectivity, but morphological diversity and variability often preclude resolving the granularity of neuron types. Combining genetic labeling with high-resolution, large-volume light microscopy, we established a single neuron anatomy platform that resolves, registers, and quantifies complete neuron morphologies in the mouse brain...
March 12, 2019: Cell Reports
Zhou Fang, Chen Weng, Haiyan Li, Ran Tao, Weihua Mai, Xiaoxiao Liu, Leina Lu, Sisi Lai, Qing Duan, Carlos Alvarez, Peter Arvan, Anthony Wynshaw-Boris, Yun Li, Yanxin Pei, Fulai Jin, Yan Li
Identification of human disease signature genes typically requires samples from many donors to achieve statistical significance. Here, we show that single-cell heterogeneity analysis may overcome this hurdle by significantly improving the test sensitivity. We analyzed the transcriptome of 39,905 single islets cells from 9 donors and observed distinct β cell heterogeneity trajectories associated with obesity or type 2 diabetes (T2D). We therefore developed RePACT, a sensitive single-cell analysis algorithm to identify both common and specific signature genes for obesity and T2D...
March 12, 2019: Cell Reports
Krystle Veerman, Claire Tardiveau, Frédéric Martins, Juliette Coudert, Jean-Philippe Girard
High-endothelial venules (HEVs) are specialized blood vessels allowing recirculation of naive lymphocytes through lymphoid organs. Here, using full-length, single-cell RNA sequencing, RNA fluorescence in situ hybridization (FISH), flow cytometry, and immunohistofluorescence, we reveal the heterogeneity of HEVs in adult mouse peripheral lymph nodes (PLNs) under conditions of homeostasis, antigenic stimulation, and after inhibition of lymphotoxin-β receptor (LTβR) signaling. We demonstrate that HEV endothelial cells are in an activated state during homeostasis, and we identify the genes characteristic of the differentiated HEV phenotype...
March 12, 2019: Cell Reports
Tapesh Santra, Ana Herrero, Javier Rodriguez, Alex von Kriegsheim, Luis F Iglesias-Martinez, Thomas Schwarzl, Des Higgins, Thin-Thin Aye, Albert J R Heck, Fernando Calvo, Lorena Agudo-Ibáñez, Piero Crespo, David Matallanas, Walter Kolch
Modern omics technologies allow us to obtain global information on different types of biological networks. However, integrating these different types of analyses into a coherent framework for a comprehensive biological interpretation remains challenging. Here, we present a conceptual framework that integrates protein interaction, phosphoproteomics, and transcriptomics data. Applying this method to analyze HRAS signaling from different subcellular compartments shows that spatially defined networks contribute specific functions to HRAS signaling...
March 12, 2019: Cell Reports
Sara Suna Yücel, Walter Stelzer, Alessandra Lorenzoni, Manfred Wozny, Dieter Langosch, Marius K Lemberg
Unspliced XBP1 mRNA encodes XBP1u, the transcriptionally inert variant of the unfolded protein response (UPR) transcription factor XBP1s. XBP1u targets its mRNA-ribosome-nascent-chain-complex to the endoplasmic reticulum (ER) to facilitate UPR activation and prevents overactivation. Yet, its membrane association is controversial. Here, we use cell-free translocation and cellular assays to define a moderately hydrophobic stretch in XBP1u that is sufficient to mediate insertion into the ER membrane. Mutagenesis of this transmembrane (TM) region reveals residues that facilitate XBP1u turnover by an ER-associated degradation route that is dependent on signal peptide peptidase (SPP)...
March 12, 2019: Cell Reports
Anthony Arceci, Thomas Bonacci, Xianxi Wang, Kyle Stewart, Jeffrey S Damrauer, Katherine A Hoadley, Michael J Emanuele
The transcription factor FOXM1 contributes to cell cycle progression and is significantly upregulated in basal-like breast cancer (BLBC). Despite its importance in normal and cancer cell cycles, we lack a complete understanding of mechanisms that regulate FOXM1. We identified USP21 in an RNAi-based screen for deubiquitinases that control FOXM1 abundance. USP21 increases the stability of FOXM1, and USP21 binds and deubiquitinates FOXM1 in vivo and in vitro, indicating a direct enzyme-substrate relationship...
March 12, 2019: Cell Reports
Ilana Chefetz, Edward Grimley, Kun Yang, Linda Hong, Ekaterina V Vinogradova, Radu Suciu, Ilya Kovalenko, David Karnak, Cynthia A Morgan, Mikhail Chtcherbinine, Cameron Buchman, Brandt Huddle, Scott Barraza, Meredith Morgan, Kara A Bernstein, Euisik Yoon, David B Lombard, Andrea Bild, Geeta Mehta, Iris Romero, Chun-Yi Chiang, Charles Landen, Benjamin Cravatt, Thomas D Hurley, Scott D Larsen, Ronald J Buckanovich
Ovarian cancer is typified by the development of chemotherapy resistance. Chemotherapy resistance is associated with high aldehyde dehydrogenase (ALDH) enzymatic activity, increased cancer "stemness," and expression of the stem cell marker CD133. As such, ALDH activity has been proposed as a therapeutic target. Although it remains controversial which of the 19 ALDH family members drive chemotherapy resistance, ALDH1A family members have been primarily linked with chemotherapy resistant and stemness...
March 12, 2019: Cell Reports
Xazmin H Lowman, Eric A Hanse, Ying Yang, Mari B Ishak Gabra, Thai Q Tran, Haiqing Li, Mei Kong
Cancer cells heavily depend on the amino acid glutamine to meet the demands associated with growth and proliferation. Due to the rapid consumption of glutamine, cancer cells frequently undergo glutamine starvation in vivo. We and others have shown that p53 is a critical regulator in metabolic stress resistance. To better understand the molecular mechanisms by which p53 activation promotes cancer cell adaptation to glutamine deprivation, we identified p53-dependent genes that are induced upon glutamine deprivation by using RNA-seq analysis...
March 12, 2019: Cell Reports
Chuan-Ming Xie, Mingjia Tan, Xiao-Tong Lin, Di Wu, Yihan Jiang, Ye Tan, Haomin Li, Yuanyuan Ma, Xiufang Xiong, Yi Sun
FBXW7 is a tumor suppressive E3 ligase, whereas RAS-ERK and mechanistic target of rapamycin kinase (mTORC1) are two major oncogenic pathways. Whether and how FBXW7 regulates these two oncogenic pathways are unknown. Here, we showed that SHOC2, a RAS activator, is a FBXW7 substrate. Growth stimuli trigger SHOC2 phosphorylation on Thr507 by the mitogen-activated protein kinase (MAPK) signal, which facilitates FBXW7 binding for ubiquitylation and degradation. FBXW7-mediated SHOC2 degradation terminates the RAS-MAPK signals and inhibits proliferation...
March 12, 2019: Cell Reports
Oliver Kluth, Mandy Stadion, Pascal Gottmann, Heja Aga, Markus Jähnert, Stephan Scherneck, Heike Vogel, Ulrika Krus, Anett Seelig, Charlotte Ling, Jantje Gerdes, Annette Schürmann
An insufficient adaptive beta-cell compensation is a hallmark of type 2 diabetes (T2D). Primary cilia function as versatile sensory antennae regulating various cellular processes, but their role on compensatory beta-cell replication has not been examined. Here, we identify a significant enrichment of downregulated, cilia-annotated genes in pancreatic islets of diabetes-prone NZO mice as compared with diabetes-resistant B6-ob/ob mice. Among 327 differentially expressed mouse cilia genes, 81 human orthologs are also affected in islets of diabetic donors...
March 12, 2019: Cell Reports
Devesh Mishra, Jennifer E Richard, Ivana Maric, Begona Porteiro, Martin Häring, Sander Kooijman, Saliha Musovic, Kim Eerola, Lorena López-Ferreras, Eduard Peris, Katarzyna Grycel, Olesya T Shevchouk, Peter Micallef, Charlotta S Olofsson, Ingrid Wernstedt Asterholm, Harvey J Grill, Ruben Nogueiras, Karolina P Skibicka
Chronic low-grade inflammation and increased serum levels of the cytokine IL-6 accompany obesity. For brain-produced IL-6, the mechanisms by which it controls energy balance and its role in obesity remain unclear. Here, we show that brain-produced IL-6 is decreased in obese mice and rats in a neuroanatomically and sex-specific manner. Reduced IL-6 mRNA localized to lateral parabrachial nucleus (lPBN) astrocytes, microglia, and neurons, including paraventricular hypothalamus-innervating lPBN neurons. IL-6 microinjection into lPBN reduced food intake and increased brown adipose tissue (BAT) thermogenesis in male lean and obese rats by increasing thyroid and sympathetic outflow to BAT...
March 12, 2019: Cell Reports
Kai Li, Chen Qiu, Peng Sun, De-Chen Liu, Ti-Jun Wu, Kai Wang, Yun-Cai Zhou, Xiao-Ai Chang, Ye Yin, Fang Chen, Yun-Xia Zhu, Xiao Han
The homeostatic balance of hepatic glucose uptake and production is exquisitely controlled by hormonal signals during feed-fast cycles. FoxO1, a transcription factor that functions in the regulation of glucose homeostasis, undergoes posttranslational modifications, such as acetylation, in response to hormonal signals, yet the mechanism remains poorly elucidated. Through expression profiling of 324 co-factors of CBP, a well-known acetyl-transferase of FoxO1, we identify Ets1 as a modulator of FoxO1 acetylation that is highly associated with feed-fast cycles...
March 12, 2019: Cell Reports
Zhimin Ou, Yanchen Ma, Yuxia Sun, Gege Zheng, Shiyun Wang, Rui Xing, Xiang Chen, Ying Han, Jiajia Wang, Q Richard Lu, Tong-Jin Zhao, Ying Chen
The CNS plays a pivotal role in energy homeostasis, but whether oligodendrocytes are involved has been largely unexplored. Here, we show that signaling through GPR17, a G-protein-coupled receptor predominantly expressed in the oligodendrocyte lineage, regulates food intake by modulating hypothalamic neuronal activities. GPR17-null mice and mice with an oligodendrocyte-specific knockout of GPR17 have lean phenotypes on a high-fat diet, suggesting that GPR17 regulates body weight by way of oligodendrocytes. Downregulation of GPR17 results in activation of cAMP-protein kinase A (PKA) signaling in oligodendrocytes and upregulated expression of pyruvate dehydrogenase kinase 1 (PDK1), which promotes lactate production...
March 12, 2019: Cell Reports
Joseph B Rayman, Joud Hijazi, Xiang Li, Nancy Kedersha, Paul J Anderson, Eric R Kandel
TIA1 is a prion-related RNA-binding protein whose capacity to form various types of intracellular aggregates has been implicated in neurodegenerative disease. However, its role in normal brain function is poorly understood. Here, we show that TIA1 bidirectionally modulates stress-dependent synaptic plasticity in the hippocampus, a brain region involved in fear memory and olfactory discrimination learning. At the behavioral level, conditioned odor avoidance is potentiated by TIA1 deletion, whereas overexpression of TIA1 in the ventral hippocampus inhibits both contextual fear memory and avoidance...
March 12, 2019: Cell Reports
Anne Sofie Munk, Wei Wang, Nicholas Burdon Bèchet, Ahmed M Eltanahy, Anne Xiaoan Cheng, Björn Sigurdsson, Abdellatif Benraiss, Maarja A Mäe, Benjamin Travis Kress, Douglas H Kelley, Christer Betsholtz, Kjeld Møllgård, Anja Meissner, Maiken Nedergaard, Iben Lundgaard
The glymphatic system is a highly polarized cerebrospinal fluid (CSF) transport system that facilitates the clearance of neurotoxic molecules through a brain-wide network of perivascular pathways. Herein we have mapped the development of the glymphatic system in mice. Perivascular CSF transport first emerges in hippocampus in newborn mice, and a mature glymphatic system is established in the cortex at 2 weeks of age. Formation of astrocytic endfeet and polarized expression of aquaporin 4 (AQP4) consistently coincided with the appearance of perivascular CSF transport...
March 12, 2019: Cell Reports
Johanna Finn, Kilian Sottoriva, Kostandin V Pajcini, Jan K Kitajewski, Chang Chen, Wei Zhang, Asrar B Malik, Yuru Liu
Lung alveolar type I cells (AT1) and alveolar type II cells (AT2) regulate the structural integrity and function of alveoli. AT1, covering ∼95% of the surface area, are responsible for gas exchange, whereas AT2 serve multiple functions, including alveolar repair through proliferation and differentiation into AT1. However, the signaling mechanisms for alveolar repair remain unclear. Here, we demonstrate, in Pseudomonas aeruginosa-induced acute lung injury in mice, that non-canonical Notch ligand Dlk1 (delta-like 1 homolog) is essential for AT2-to-AT1 differentiation...
March 12, 2019: Cell Reports
Chiara Naro, Livia Pellegrini, Ariane Jolly, Donatella Farini, Eleonora Cesari, Pamela Bielli, Pierre de la Grange, Claudio Sette
Male germ cells express the widest repertoire of transcript variants in mammalian tissues. Nevertheless, factors and mechanisms underlying such pronounced diversity are largely unknown. The splicing regulator Sam68 is highly expressed in meiotic cells, and its ablation results in defective spermatogenesis. Herein, we uncover an extensive splicing program operated by Sam68 across meiosis, primarily characterized by alternative last exon (ALE) regulation in genes of functional relevance for spermatogenesis. Lack of Sam68 preferentially causes premature transcript termination at internal polyadenylation sites, a feature observed also upon depletion of the spliceosomal U1snRNP in somatic cells...
March 12, 2019: Cell Reports
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