DOCSLIB.ORG

The Borg Family of Cdc42 Effector Proteins Cdc42ep1–5

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
The Borg Family of Cdc42 Effector Proteins Cdc42ep1–5 View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Institute of Cancer Research Repository Biochemical Society Transactions (2016) 0 1–8 DOI: 10.1042/BST20160219 1 2 The Borg family of Cdc42 effector proteins 3 4 Cdc42EP1–5 5 6 Aaron J. Farrugia and Fernando Calvo 7 8 Tumour Microenvironment Team, Division of Cancer Biology, Institute of Cancer Research, 237 Fulham Road, London SW2 6JB, U.K. 9 Correspondence: Fernando Calvo ([email protected]) 10 11 12 13 Despite being discovered more than 15 years ago, the Borg (binder of Rho GTPases) 14 – family of Cdc42 effector proteins (Cdc42EP1 5) remains largely uncharacterised and rela- 15 tively little is known about their structure, regulation and role in development and disease. 16 Recent studies are starting to unravel some of the key functional and mechanistic 17 aspects of the Borg proteins, including their role in cytoskeletal remodelling and signal- 18 ling. In addition, the participation of Borg proteins in important cellular processes such as 19 cell shape, directed migration and differentiation is slowly emerging, directly linking Borgs 20 with important physiological and pathological processes such as angiogenesis, neuro- 21 fi transmission and cancer-associated desmoplasia. Here, we review some of these nd- 22 ings and discuss future prospects. 23 24 25 26 27 28 29 Introduction 30 The Rho GTPase family member Cdc42 regulates a diverse range of cellular functions including cyto- 31 kinesis, cytoskeletal remodelling and cell polarity [1,2]. Like other Rho family members, Cdc42 cycles 32 between two tightly regulated conformational states, a GTP-bound active state and a GDP-bound 33 inactive state [3]. Activated Cdc42 exerts its functions by interacting with downstream effectors con- 34 taining a Cdc42/Rac interaction binding (CRIB) motif [3,4]. Several Cdc42 effector proteins, including 35Q1 ¶ kinases and scaffolds, have been well characterised [5]; however, the functions of others remain rela- 36 tively unknown. Still, elusive is the largely understudied Borg family of Cdc42 effector proteins, 37 Cdc42EP1–5[6,7]. 38 Borg proteins were simultaneously discovered by two independent groups as proteins that interact 39 with the Rho GTPases Cdc42 and TC10/RhoQ [6,7]. Using a two-hybrid screen for interactors of 40Q2 ¶ TC10, the group of Ian Macara identified three clones containing identical CRIB motifs and flanking 41 regions. Further analysis discovered the ability of these clones to bind active Cdc42 but not to Rac or 42 Rho GTPases. These initial clones were subsequently extended to five putative clones based on 43 sequence homology and their ability to bind Cdc42 in a GTP-dependent manner. They named this 44 new family the Borg (binder of Rho GTPases) proteins (Borg1–5). One of these clones was the previ- 45 ously identified MSE55 [8], which was renamed Borg5. MSE55/Borg5 had already been shown to 46 contain a functional CRIB domain in its N-terminus and to be a non-kinase effector protein of Cdc42 47 capable of inducing F-actin-based protrusions [9]. Based on these characteristics, the group of Perter 48 Burbelo used the amino acid sequence of MSE55/Borg5 to search for homologous sequences and 49 Received: 30 July 2016 identified the same five clones [7]. They named the family ‘Cdc42 effector proteins’ or Cdc42EP/CEP, 50 Revised: 15 September 2016 which led to the disparate nomenclature for each member (depending on the classification): MSE55/ 51 Accepted: 19 September 2016 Cdc42EP1/Borg5, Cdc42EP2/Borg1, Cdc42EP3/Borg2, Cdc42EP4/Borg4 and Cdc42EP5/Borg3. For 52 Version of Record published: clarity, here we use the HUGO gene nomenclature to refer to each member (i.e. Cdc42EP1 instead of 53 0 Month 2016 MSE55/Borg5), but may use the term Borg to refer to the family. 54 © 2016 The Author(s). This is an open access article published by Portland Press Limited on behalf of the Biochemical Society and distributed under the Creative Commons Attribution License 4.0 (CC BY). 1 Biochemical Society Transactions (2016) 0 1–8 DOI: 10.1042/BST20160219 55 56 57 58 59 60 61 62 63 64 65 66 67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 Figure 1. Cdc42EP/Borg family of Cdc42 effector proteins. 87 (A) Schematic diagram showing the different domains in all the Borg proteins. (B) Direct alignments of the CRIB domains of 88 murine Cdc42EP1–5, with conserved residues highlighted. (C) Direct alignments of the BH3 domain of murine Cdc42EP1–5, Q7 89 with conserved residues highlighted. ¶ 90 91 92 93 Structure 94 Borg proteins are relatively small in size, ranging from 150 amino acids (∼15.5 kDa) in Cdc42EP5 to 409 95 amino acids (∼39 kDa) in Cdc42EP1 (Figure 1A). No family member presents known enzymatically active 96 domains, which suggest that they may exert their biological functions via structural or scaffolding activities. All 97 Borg proteins are characterised by the presence of a highly homologous N-terminal CRIB domain (Figure 1B) 98 [6,7]. In Borgs, the CRIB domain presents an extension at the C-terminus that may mediate its specific binding 99 to active Cdc42 and TC10 but not to Rac1 [6,7], as well as determining part of the particular biological effects 100 of these proteins. Following the CRIB motif, there is a well-conserved short domain that is unique to Borg pro- 101 teins and that was defined as the Borg Homology (BH) 1 domain [6]. The central and C-terminal parts of the 102 proteins are more divergent, but still present two additional well-conserved regions termed BH2 and BH3. The 103 BH2 domain is absent in the smallest Borg, Cdc42EP5, whereas the BH3 domain is common to all Borgs. The 104 BH3 domain has a central location in Cdc42EP1 and Cdc42EP4, whereas it is localised at the C-terminal parts 105 of Cdc42EP2, Cdc42EP3 and Cdc42EP5 (Figure 1C). The BH3 domain is the only BH domain with a defined 106 molecular role and has been shown to be necessary and sufficient for the specific binding of Borgs to septins 107 [10] (see Box 1). Contrary to the BH3 domain, the roles of the BH1 and BH2 domains are still to be defined. 108 2 © 2016 The Author(s). This is an open access article published by Portland Press Limited on behalf of the Biochemical Society and distributed under the Creative Commons Attribution License 4.0 (CC BY). Biochemical Society Transactions (2016) 0 1–8 DOI: 10.1042/BST20160219 109 110 Box 1. The septin cytoskeleton 111 112 Septins comprise a large family of proteins (13 genes and >30 protein isoforms in humans) with 113 ubiquitous and tissue-specific expressions [12]. Septins are GTP-binding proteins that participate 114 in numerous cellular processes, including cell division, cell polarity and cytoskeletal organisation 115 [13,14]. Septins can dimerise and assemble into oligomers, such as the SEPT2/6/7/9 polymer, 116 which is the best characterised in mammalian cells [15,16]. Septin oligomers can assemble into 117 higher-order structures such as filaments, bundled filaments and rings, which can serve as scaf- 118 folds and diffusion barriers that control the localisation of cellular proteins [17]. The septin fila- 119 mentous network can associate with cell membranes and has been shown to co-localise with 120 actin, tubulin and other cytoskeletal components [18,19]; thus, septins are increasingly recog- 121 nised as a novel component of the cytoskeleton [13]. In addition to the improved understanding 122 of the biochemical properties and functions of septins, a growing number of studies are highlight- 123 ing the relevance of septins in the development and physiology of specific tissues and organs 124 [12]. 125 126 127 Outside the CRIB and BH domains, sequence divergences emerge. The central regions of Cdc42EP1, 128 Cdc42EP2 and Cdc42EP5 present a proline-rich domain; in addition, Cdc42EP1 contains several heptad 129 repeats that follow the BH3 domain [10]. More recently, it has been described that Cdc42EP3 presents a puta- 130 tive actin-binding region in its central region, C-terminally to the BH2 domain (Figure 1A)[11]. This region 131 presents high homology to the actin bundling region of Anillin. This particular actin-binding region of 132 Cdc42EP3 is not conserved among Borg proteins; however, other Borg members may bind and/or modulate 133 the actin cytoskeleton by alternative mechanisms or via distinct domains. 134 135 Mode of action 136 137 Q3 At cellular and molecular levels, the function of Borg proteins remains to be clearly defined, but studies thus 138 ¶ far indicate relevant roles in cytoskeletal rearrangement. As with other Cdc42 effector proteins, Borg proteins 139 were initially linked to the regulation of cell shape and early gain-of-function experiments were described roles 140 141 142 Table 1 The major interactions and functions of Borg proteins Q8 ¶ 143 CDC42 144 effector Binding 145 protein Interactions partners Reported functions Key references 146 Cdc42EP1 Cdc42, TC10 (RhoQ), SEPT2/6/7 Cell shape regulation, [6,7,9,10,20,21,33,34] 147 (Borg5, aPKC, ERK2, multiple actomyosin contractility, cell 148 MSE55) sites identified by migration of endothelial cells 149 proteomic analysis and trophectoderm cells, directionality and 150 persistence, angiogenesis Q9 151 ¶ Cdc42EP2 Cdc42, TC10, ERK2, SEPT2/6/7 Cell shape regulation and [6,7,10,20,32,33,37] 152 (Borg1) ERK3, MK5 regulator of myogenesis 153 154 Cdc42EP3 Cdc42, TC10, ERK3, SEPT2/6/7 Cell shape regulation, [6,7,10,11,20,31,32] (Borg2) MK5 F-actin actomyosin contractility and 155 pathological fibroblast 156 activation 157 Cdc42EP4 Cdc42, TC10, PKCα SEPT2/6/7, Cell shape regulation, [6,7,10,20,23,24] 158 (Borg4) ARHGEF17 filopodia formation and 159 (TEM4) mammary cell migration 160 Cdc42EP5 Cdc42, ERK3, MK5 SEPT2/6/7 Cell shape regulation and [6,7,10,20,32] 161 (Borg3) lamellipodium formation 162 © 2016 The Author(s).
Load more

Recommended publications
  • PARSANA-DISSERTATION-2020.Pdf
    DECIPHERING TRANSCRIPTIONAL PATTERNS OF GENE REGULATION: A COMPUTATIONAL APPROACH by Princy Parsana A dissertation submitted to The Johns Hopkins University in conformity with the requirements for the degree of Doctor of Philosophy Baltimore, Maryland July, 2020 © 2020 Princy Parsana All rights reserved Abstract With rapid advancements in sequencing technology, we now have the ability to sequence the entire human genome, and to quantify expression of tens of thousands of genes from hundreds of individuals. This provides an extraordinary opportunity to learn phenotype relevant genomic patterns that can improve our understanding of molecular and cellular processes underlying a trait. The high dimensional nature of genomic data presents a range of computational and statistical challenges. This dissertation presents a compilation of projects that were driven by the motivation to efficiently capture gene regulatory patterns in the human transcriptome, while addressing statistical and computational challenges that accompany this data. We attempt to address two major difficulties in this domain: a) artifacts and noise in transcriptomic data, andb) limited statistical power. First, we present our work on investigating the effect of artifactual variation in gene expression data and its impact on trans-eQTL discovery. Here we performed an in-depth analysis of diverse pre-recorded covariates and latent confounders to understand their contribution to heterogeneity in gene expression measurements. Next, we discovered 673 trans-eQTLs across 16 human tissues using v6 data from the Genotype Tissue Expression (GTEx) project. Finally, we characterized two trait-associated trans-eQTLs; one in Skeletal Muscle and another in Thyroid. Second, we present a principal component based residualization method to correct gene expression measurements prior to reconstruction of co-expression networks.
    [Show full text]
  • Dedifferentiation by Adenovirus E1A Due to Inactivation of Hippo Pathway Effectors YAP and TAZ
    Downloaded from genesdev.cshlp.org on October 3, 2021 - Published by Cold Spring Harbor Laboratory Press Dedifferentiation by adenovirus E1A due to inactivation of Hippo pathway effectors YAP and TAZ Nathan R. Zemke, Dawei Gou, and Arnold J. Berk Molecular Biology Institute, University of California at Los Angeles, Los Angeles, California 90095, USA Adenovirus transformed cells have a dedifferentiated phenotype. Eliminating E1A in transformed human embryonic kidney cells derepressed ∼2600 genes, generating a gene expression profile closely resembling mesenchymal stem cells (MSCs). This was associated with a dramatic change in cell morphology from one with scant cytoplasm and a globular nucleus to one with increased cytoplasm, extensive actin stress fibers, and actomyosin-dependent flat- tening against the substratum. E1A-induced hypoacetylation at histone H3 Lys27 and Lys18 (H3K27/18) was reversed. Most of the increase in H3K27/18ac was in enhancers near TEAD transcription factors bound by Hippo signaling-regulated coactivators YAP and TAZ. E1A causes YAP/TAZ cytoplasmic sequestration. After eliminating E1A, YAP/TAZ were transported into nuclei, where they associated with poised enhancers with DNA-bound TEAD4 and H3K4me1. This activation of YAP/TAZ required RHO family GTPase signaling and caused histone acetylation by p300/CBP, chromatin remodeling, and cohesin loading to establish MSC-associated enhancers and then superenhancers. Consistent results were also observed in primary rat embryo kidney cells, human fibroblasts, and human respiratory tract epithelial cells. These results together with earlier studies suggest that YAP/TAZ function in a developmental checkpoint controlled by signaling from the actin cytoskeleton that prevents differ- entiation of a progenitor cell until it is in the correct cellular and tissue environment.
    [Show full text]
  • Mechanical Forces Induce an Asthma Gene Signature in Healthy Airway Epithelial Cells Ayşe Kılıç1,10, Asher Ameli1,2,10, Jin-Ah Park3,10, Alvin T
    www.nature.com/scientificreports OPEN Mechanical forces induce an asthma gene signature in healthy airway epithelial cells Ayşe Kılıç1,10, Asher Ameli1,2,10, Jin-Ah Park3,10, Alvin T. Kho4, Kelan Tantisira1, Marc Santolini 1,5, Feixiong Cheng6,7,8, Jennifer A. Mitchel3, Maureen McGill3, Michael J. O’Sullivan3, Margherita De Marzio1,3, Amitabh Sharma1, Scott H. Randell9, Jefrey M. Drazen3, Jefrey J. Fredberg3 & Scott T. Weiss1,3* Bronchospasm compresses the bronchial epithelium, and this compressive stress has been implicated in asthma pathogenesis. However, the molecular mechanisms by which this compressive stress alters pathways relevant to disease are not well understood. Using air-liquid interface cultures of primary human bronchial epithelial cells derived from non-asthmatic donors and asthmatic donors, we applied a compressive stress and then used a network approach to map resulting changes in the molecular interactome. In cells from non-asthmatic donors, compression by itself was sufcient to induce infammatory, late repair, and fbrotic pathways. Remarkably, this molecular profle of non-asthmatic cells after compression recapitulated the profle of asthmatic cells before compression. Together, these results show that even in the absence of any infammatory stimulus, mechanical compression alone is sufcient to induce an asthma-like molecular signature. Bronchial epithelial cells (BECs) form a physical barrier that protects pulmonary airways from inhaled irritants and invading pathogens1,2. Moreover, environmental stimuli such as allergens, pollutants and viruses can induce constriction of the airways3 and thereby expose the bronchial epithelium to compressive mechanical stress. In BECs, this compressive stress induces structural, biophysical, as well as molecular changes4,5, that interact with nearby mesenchyme6 to cause epithelial layer unjamming1, shedding of soluble factors, production of matrix proteins, and activation matrix modifying enzymes, which then act to coordinate infammatory and remodeling processes4,7–10.
    [Show full text]
  • Regulation of Cdc42 and Its Effectors in Epithelial Morphogenesis Franck Pichaud1,2,*, Rhian F
    © 2019. Published by The Company of Biologists Ltd | Journal of Cell Science (2019) 132, jcs217869. doi:10.1242/jcs.217869 REVIEW SUBJECT COLLECTION: ADHESION Regulation of Cdc42 and its effectors in epithelial morphogenesis Franck Pichaud1,2,*, Rhian F. Walther1 and Francisca Nunes de Almeida1 ABSTRACT An overview of Cdc42 Cdc42 – a member of the small Rho GTPase family – regulates cell Cdc42 was discovered in yeast and belongs to a large family of small – polarity across organisms from yeast to humans. It is an essential (20 30 kDa) GTP-binding proteins (Adams et al., 1990; Johnson regulator of polarized morphogenesis in epithelial cells, through and Pringle, 1990). It is part of the Ras-homologous Rho subfamily coordination of apical membrane morphogenesis, lumen formation and of GTPases, of which there are 20 members in humans, including junction maturation. In parallel, work in yeast and Caenorhabditis elegans the RhoA and Rac GTPases, (Hall, 2012). Rho, Rac and Cdc42 has provided important clues as to how this molecular switch can homologues are found in all eukaryotes, except for plants, which do generate and regulate polarity through localized activation or inhibition, not have a clear homologue for Cdc42. Together, the function of and cytoskeleton regulation. Recent studies have revealed how Rho GTPases influences most, if not all, cellular processes. important and complex these regulations can be during epithelial In the early 1990s, seminal work from Alan Hall and his morphogenesis. This complexity is mirrored by the fact that Cdc42 can collaborators identified Rho, Rac and Cdc42 as main regulators of exert its function through many effector proteins.
    [Show full text]
  • Defining Functional Interactions During Biogenesis of Epithelial Junctions
    ARTICLE Received 11 Dec 2015 | Accepted 13 Oct 2016 | Published 6 Dec 2016 | Updated 5 Jan 2017 DOI: 10.1038/ncomms13542 OPEN Defining functional interactions during biogenesis of epithelial junctions J.C. Erasmus1,*, S. Bruche1,*,w, L. Pizarro1,2,*, N. Maimari1,3,*, T. Poggioli1,w, C. Tomlinson4,J.Lees5, I. Zalivina1,w, A. Wheeler1,w, A. Alberts6, A. Russo2 & V.M.M. Braga1 In spite of extensive recent progress, a comprehensive understanding of how actin cytoskeleton remodelling supports stable junctions remains to be established. Here we design a platform that integrates actin functions with optimized phenotypic clustering and identify new cytoskeletal proteins, their functional hierarchy and pathways that modulate E-cadherin adhesion. Depletion of EEF1A, an actin bundling protein, increases E-cadherin levels at junctions without a corresponding reinforcement of cell–cell contacts. This unexpected result reflects a more dynamic and mobile junctional actin in EEF1A-depleted cells. A partner for EEF1A in cadherin contact maintenance is the formin DIAPH2, which interacts with EEF1A. In contrast, depletion of either the endocytic regulator TRIP10 or the Rho GTPase activator VAV2 reduces E-cadherin levels at junctions. TRIP10 binds to and requires VAV2 function for its junctional localization. Overall, we present new conceptual insights on junction stabilization, which integrate known and novel pathways with impact for epithelial morphogenesis, homeostasis and diseases. 1 National Heart and Lung Institute, Faculty of Medicine, Imperial College London, London SW7 2AZ, UK. 2 Computing Department, Imperial College London, London SW7 2AZ, UK. 3 Bioengineering Department, Faculty of Engineering, Imperial College London, London SW7 2AZ, UK. 4 Department of Surgery & Cancer, Faculty of Medicine, Imperial College London, London SW7 2AZ, UK.
    [Show full text]
  • Genome-Wide Analysis of Transcriptional Bursting-Induced Noise in Mammalian Cells
    bioRxiv preprint doi: https://doi.org/10.1101/736207; this version posted August 15, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. Title: Genome-wide analysis of transcriptional bursting-induced noise in mammalian cells Authors: Hiroshi Ochiai1*, Tetsutaro Hayashi2, Mana Umeda2, Mika Yoshimura2, Akihito Harada3, Yukiko Shimizu4, Kenta Nakano4, Noriko Saitoh5, Hiroshi Kimura6, Zhe Liu7, Takashi Yamamoto1, Tadashi Okamura4,8, Yasuyuki Ohkawa3, Itoshi Nikaido2,9* Affiliations: 1Graduate School of Integrated Sciences for Life, Hiroshima University, Higashi-Hiroshima, Hiroshima, 739-0046, Japan 2Laboratory for Bioinformatics Research, RIKEN BDR, Wako, Saitama, 351-0198, Japan 3Division of Transcriptomics, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Fukuoka, 812-0054, Japan 4Department of Animal Medicine, National Center for Global Health and Medicine (NCGM), Tokyo, 812-0054, Japan 5Division of Cancer Biology, The Cancer Institute of JFCR, Tokyo, 135-8550, Japan 6Graduate School of Bioscience and Biotechnology, Tokyo Institute of Technology, Yokohama, Kanagawa, 226-8503, Japan 7Janelia Research Campus, Howard Hughes Medical Institute, Ashburn, VA, 20147, USA 8Section of Animal Models, Department of Infectious Diseases, National Center for Global Health and Medicine (NCGM), Tokyo, 812-0054, Japan 9Bioinformatics Course, Master’s/Doctoral Program in Life Science Innovation (T-LSI), School of Integrative and Global Majors (SIGMA), University of Tsukuba, Wako, 351-0198, Japan *Corresponding authors Corresponding authors e-mail addresses Hiroshi Ochiai, [email protected] Itoshi Nikaido, [email protected] bioRxiv preprint doi: https://doi.org/10.1101/736207; this version posted August 15, 2019.
    [Show full text]
  • Understanding the Role of the Chromosome 15Q25.1 in COPD Through Epigenetics and Transcriptomics
    European Journal of Human Genetics (2018) 26:709–722 https://doi.org/10.1038/s41431-017-0089-8 ARTICLE Understanding the role of the chromosome 15q25.1 in COPD through epigenetics and transcriptomics 1 1,2 1,3,4 5,6 5,6 Ivana Nedeljkovic ● Elena Carnero-Montoro ● Lies Lahousse ● Diana A. van der Plaat ● Kim de Jong ● 5,6 5,7 6 8 9 10 Judith M. Vonk ● Cleo C. van Diemen ● Alen Faiz ● Maarten van den Berge ● Ma’en Obeidat ● Yohan Bossé ● 11 1,12 12 1 David C. Nickle ● BIOS Consortium ● Andre G. Uitterlinden ● Joyce J. B. van Meurs ● Bruno C. H. Stricker ● 1,4,13 6,8 5,6 1 1 Guy G. Brusselle ● Dirkje S. Postma ● H. Marike Boezen ● Cornelia M. van Duijn ● Najaf Amin Received: 14 March 2017 / Revised: 6 November 2017 / Accepted: 19 December 2017 / Published online: 8 February 2018 © The Author(s) 2018. This article is published with open access Abstract Chronic obstructive pulmonary disease (COPD) is a major health burden in adults and cigarette smoking is considered the most important environmental risk factor of COPD. Chromosome 15q25.1 locus is associated with both COPD and smoking. Our study aims at understanding the mechanism underlying the association of chromosome 15q25.1 with COPD through epigenetic and transcriptional variation in a population-based setting. To assess if COPD-associated variants in 1234567890();,: 15q25.1 are methylation quantitative trait loci, epigenome-wide association analysis of four genetic variants, previously associated with COPD (P < 5 × 10−8) in the 15q25.1 locus (rs12914385:C>T-CHRNA3, rs8034191:T>C-HYKK, rs13180: C>T-IREB2 and rs8042238:C>T-IREB2), was performed in the Rotterdam study (n = 1489).
    [Show full text]
  • Differentially Expressed on Collagen Networks 1, 2, 10 © 2000-2009 Ingenuity Systems, Inc. All Rights Reserved. Symbol Entrez
    Differentially expressed on collagen Networks 1, 2, 10 © 2000-2009 Ingenuity Systems, Inc. All rights reserved. Symbol Entrez Gene Name Affymetrix Fold Change Location Family ALDH1A3 aldehyde dehydrogenase 1 family, member A3 203180_at -5.43125168 Cytoplasm enzyme 209772_s_ Plasma CD24 CD24 molecule at -4.32890229 Membrane other HSD11B2 hydroxysteroid (11-beta) dehydrogenase 2 204130_at -4.1099197 Cytoplasm enzyme Plasma AMOTL2 angiomotin like 2 203002_at -2.82872773 Membrane other transcription DLX2 distal-less homeobox 2 207147_at -2.74996362 Nucleus regulator 221215_s_ RIPK4 receptor-interacting serine-threonine kinase 4 at -2.56556472 Nucleus kinase PLK2 polo-like kinase 2 (Drosophila) 201939_at -2.47054478 Nucleus kinase ALDH3A1 aldehyde dehydrogenase 3 family, memberA1 205623_at -2.30532989 Cytoplasm enzyme TXNRD1 thioredoxin reductase 1 201266_at -2.27936909 Cytoplasm enzyme Extracellular CYR61 cysteine-rich, angiogenic inducer, 61 201289_at -2.09052668 Space other 214212_x_ FERMT2 fermitin family homolog 2 (Drosophila) at -1.87478183 Cytoplasm other Plasma RIT1 Ras-like without CAAX 1 209882_at -1.77586775 Membrane enzyme 210297_s_ Extracellular MSMB microseminoprotein, beta- at -1.72177723 Space other Extracellular PI3 peptidase inhibitor 3, skin-derived 203691_at -1.68135697 Space other ALDH3B1 aldehyde dehydrogenase 3 family, member B1 205640_at -1.67376791 Cytoplasm enzyme 202124_s_ Plasma TRAK2 trafficking protein, kinesin binding 2 at -1.6367793 Membrane transporter BMP and activin membrane-bound inhibitor Plasma BAMBI
    [Show full text]
  • Transcriptome Sequencing and Genome-Wide Association Analyses Reveal Lysosomal Function and Actin Cytoskeleton Remodeling in Schizophrenia and Bipolar Disorder
    Molecular Psychiatry (2015) 20, 563–572 © 2015 Macmillan Publishers Limited All rights reserved 1359-4184/15 www.nature.com/mp ORIGINAL ARTICLE Transcriptome sequencing and genome-wide association analyses reveal lysosomal function and actin cytoskeleton remodeling in schizophrenia and bipolar disorder Z Zhao1,6,JXu2,6, J Chen3,6, S Kim4, M Reimers3, S-A Bacanu3,HYu1, C Liu5, J Sun1, Q Wang1, P Jia1,FXu2, Y Zhang2, KS Kendler3, Z Peng2 and X Chen3 Schizophrenia (SCZ) and bipolar disorder (BPD) are severe mental disorders with high heritability. Clinicians have long noticed the similarities of clinic symptoms between these disorders. In recent years, accumulating evidence indicates some shared genetic liabilities. However, what is shared remains elusive. In this study, we conducted whole transcriptome analysis of post-mortem brain tissues (cingulate cortex) from SCZ, BPD and control subjects, and identified differentially expressed genes in these disorders. We found 105 and 153 genes differentially expressed in SCZ and BPD, respectively. By comparing the t-test scores, we found that many of the genes differentially expressed in SCZ and BPD are concordant in their expression level (q ⩽ 0.01, 53 genes; q ⩽ 0.05, 213 genes; q ⩽ 0.1, 885 genes). Using genome-wide association data from the Psychiatric Genomics Consortium, we found that these differentially and concordantly expressed genes were enriched in association signals for both SCZ (Po10 − 7) and BPD (P = 0.029). To our knowledge, this is the first time that a substantially large number of genes show concordant expression and association for both SCZ and BPD. Pathway analyses of these genes indicated that they are involved in the lysosome, Fc gamma receptor-mediated phagocytosis, regulation of actin cytoskeleton pathways, along with several cancer pathways.
    [Show full text]
  • S41467-020-18249-3.Pdf
    ARTICLE https://doi.org/10.1038/s41467-020-18249-3 OPEN Pharmacologically reversible zonation-dependent endothelial cell transcriptomic changes with neurodegenerative disease associations in the aged brain Lei Zhao1,2,17, Zhongqi Li 1,2,17, Joaquim S. L. Vong2,3,17, Xinyi Chen1,2, Hei-Ming Lai1,2,4,5,6, Leo Y. C. Yan1,2, Junzhe Huang1,2, Samuel K. H. Sy1,2,7, Xiaoyu Tian 8, Yu Huang 8, Ho Yin Edwin Chan5,9, Hon-Cheong So6,8, ✉ ✉ Wai-Lung Ng 10, Yamei Tang11, Wei-Jye Lin12,13, Vincent C. T. Mok1,5,6,14,15 &HoKo 1,2,4,5,6,8,14,16 1234567890():,; The molecular signatures of cells in the brain have been revealed in unprecedented detail, yet the ageing-associated genome-wide expression changes that may contribute to neurovas- cular dysfunction in neurodegenerative diseases remain elusive. Here, we report zonation- dependent transcriptomic changes in aged mouse brain endothelial cells (ECs), which pro- minently implicate altered immune/cytokine signaling in ECs of all vascular segments, and functional changes impacting the blood–brain barrier (BBB) and glucose/energy metabolism especially in capillary ECs (capECs). An overrepresentation of Alzheimer disease (AD) GWAS genes is evident among the human orthologs of the differentially expressed genes of aged capECs, while comparative analysis revealed a subset of concordantly downregulated, functionally important genes in human AD brains. Treatment with exenatide, a glucagon-like peptide-1 receptor agonist, strongly reverses aged mouse brain EC transcriptomic changes and BBB leakage, with associated attenuation of microglial priming. We thus revealed tran- scriptomic alterations underlying brain EC ageing that are complex yet pharmacologically reversible.
    [Show full text]
  • Supplemental Information
    Supplemental information Dissection of the genomic structure of the miR-183/96/182 gene. Previously, we showed that the miR-183/96/182 cluster is an intergenic miRNA cluster, located in a ~60-kb interval between the genes encoding nuclear respiratory factor-1 (Nrf1) and ubiquitin-conjugating enzyme E2H (Ube2h) on mouse chr6qA3.3 (1). To start to uncover the genomic structure of the miR- 183/96/182 gene, we first studied genomic features around miR-183/96/182 in the UCSC genome browser (http://genome.UCSC.edu/), and identified two CpG islands 3.4-6.5 kb 5’ of pre-miR-183, the most 5’ miRNA of the cluster (Fig. 1A; Fig. S1 and Seq. S1). A cDNA clone, AK044220, located at 3.2-4.6 kb 5’ to pre-miR-183, encompasses the second CpG island (Fig. 1A; Fig. S1). We hypothesized that this cDNA clone was derived from 5’ exon(s) of the primary transcript of the miR-183/96/182 gene, as CpG islands are often associated with promoters (2). Supporting this hypothesis, multiple expressed sequences detected by gene-trap clones, including clone D016D06 (3, 4), were co-localized with the cDNA clone AK044220 (Fig. 1A; Fig. S1). Clone D016D06, deposited by the German GeneTrap Consortium (GGTC) (http://tikus.gsf.de) (3, 4), was derived from insertion of a retroviral construct, rFlpROSAβgeo in 129S2 ES cells (Fig. 1A and C). The rFlpROSAβgeo construct carries a promoterless reporter gene, the β−geo cassette - an in-frame fusion of the β-galactosidase and neomycin resistance (Neor) gene (5), with a splicing acceptor (SA) immediately upstream, and a polyA signal downstream of the β−geo cassette (Fig.
    [Show full text]
  • MECHANISMS in ENDOCRINOLOGY: Novel Genetic Causes of Short Stature
    J M Wit and others Genetics of short stature 174:4 R145–R173 Review MECHANISMS IN ENDOCRINOLOGY Novel genetic causes of short stature 1 1 2 2 Jan M Wit , Wilma Oostdijk , Monique Losekoot , Hermine A van Duyvenvoorde , Correspondence Claudia A L Ruivenkamp2 and Sarina G Kant2 should be addressed to J M Wit Departments of 1Paediatrics and 2Clinical Genetics, Leiden University Medical Center, PO Box 9600, 2300 RC Leiden, Email The Netherlands [email protected] Abstract The fast technological development, particularly single nucleotide polymorphism array, array-comparative genomic hybridization, and whole exome sequencing, has led to the discovery of many novel genetic causes of growth failure. In this review we discuss a selection of these, according to a diagnostic classification centred on the epiphyseal growth plate. We successively discuss disorders in hormone signalling, paracrine factors, matrix molecules, intracellular pathways, and fundamental cellular processes, followed by chromosomal aberrations including copy number variants (CNVs) and imprinting disorders associated with short stature. Many novel causes of GH deficiency (GHD) as part of combined pituitary hormone deficiency have been uncovered. The most frequent genetic causes of isolated GHD are GH1 and GHRHR defects, but several novel causes have recently been found, such as GHSR, RNPC3, and IFT172 mutations. Besides well-defined causes of GH insensitivity (GHR, STAT5B, IGFALS, IGF1 defects), disorders of NFkB signalling, STAT3 and IGF2 have recently been discovered. Heterozygous IGF1R defects are a relatively frequent cause of prenatal and postnatal growth retardation. TRHA mutations cause a syndromic form of short stature with elevated T3/T4 ratio. Disorders of signalling of various paracrine factors (FGFs, BMPs, WNTs, PTHrP/IHH, and CNP/NPR2) or genetic defects affecting cartilage extracellular matrix usually cause disproportionate short stature.
    [Show full text]