DOCSLIB.ORG

Gene Section Review

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Gene Section Review Atlas of Genetics and Cytogenetics in Oncology and Haematology OPEN ACCESS JOURNAL INIST-CNRS Gene Section Review SNX3 (Sorting Nexin 3) Esra Cicek, Ayca Circir Hatil, Merve Oyken, Harun Cingoz, A.Elif Erson-Bensan Department of Biological Sciences, Middle East Technical University, Ankara/TURKEY, [email protected]; [email protected]; [email protected]; [email protected]; [email protected] Published in Atlas Database: December 2019 Online updated version : http://AtlasGeneticsOncology.org/Genes/SNX3ID43757ch6q21.html Printable original version : http://documents.irevues.inist.fr/bitstream/handle/2042/70783/12-2019-SNX3ID43757ch6q21.pdf DOI: 10.4267/2042/70783 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2020 Atlas of Genetics and Cytogenetics in Oncology and Haematology Abstract Identity Sorting Nexin 3 (SNX3) gene maps to chromosome Other names: SDP3; Grd19; MCOPS8 6, minus strand and has 4 exons and 3 introns. There HGNC (Hugo): SNX3 are 3 alternatively spliced isoforms (transcripts). Location: 6q21 SNX3 is a member of the sorting nexin family. Members of this family generally have BAR Local order domains and phosphoinositide binding regions From centromere to telomere: OSTM1-AS1, called the phox (PX) domain, and are involved in NR2E1, SNX3, RNA5SP212, RNU6-1144P, intracellular trafficking. Unlike other sorting nexins, AFG1L, RPL36AP24. SNX3 does not contain a BAR domain. SNX3 protein interacts with phosphatidylinositol-3- DNA/RNA phosphates, and is involved in protein trafficking SNX3 gene consists of 4 exons and 3 introns. The through its role in the retromer complex. gene maps to 6q21 and is 49,819 kb long (NCBI Keywords Reference Sequence: NC_000006.12 : 108211217- Sorting Nexin 3, protein trafficking 108261260). Highlighted in red is protein coding sequence from exons 1-4. Figure 1. Local order of SNX3 is shown together with leading and subsequent genes on chromosome 6. The direction of arrows indicates transcriptional direction on the chromosome and arrow sizes approximate gene sizes. Atlas Genet Cytogenet Oncol Haematol. 2020; 24(9) 333 PARP1 (poly(ADP-ribose) polymerase 1) Tunçer S, Kavak K Figure 2. SNX3 gene has 4 exons and 3 introns. Numbers indicate the exons. Red boxes represents exons/ protein- coding regions and blue boxes represent untranslated regions. Description Description SNX3 gene is 49,819 kb long and is on the minus SNX3 is a small protein of 162 amino acids. strand. SNX3 gene has 4 exons. Molecular weight of the protein is 18,762 Da. Transcription Expression SNX3 produces 4 coding transcripts (1755 bp, 1072 SNX3 is expressed in brain, eye, endocrine tissues, bp, 890 bp and 1537 bp) and there is non-sense lung, proximal digestive tract, gastrointestinal tract, mediated decay for a transcript (1537 bp). liver and gallbladder, pancreas, kidney and urinary Alternative polyadenylation (APA) also creates 2 bladder, male tissues, female tissues, muscle tissues, different isoforms which has short (636 bp) or long adipose and soft tissue, skin, bone marrow and (934 bp) untranslated regions (UTRs) (Akman et.al., lymphoid tissues and blood. (The Human Protein 2015). Atlas, http://www.proteinatlas.org/). Pseudogene Localisation There are 2 pseudogenes of SNX3 which are: SNX3 protein is mostly localized to the endosomes SNX3P1Y (sorting nexin 3 pseudogene 1 Y-linked) with the retromer complex (M. Harterink, 2011). on chromosome Y and SNX3P1X (sorting nexin 3 Function pseudogene 1 X-linked) on X chromosome (NCBI, 2018). SNX3 functions within the retromer complex. There is no data available for SNX3P1Y expression. Among other members of the nexins, only SNX3 is There are RNAseq data results showing SNX3P1X indispensable for recognition and recycling of WLS is expressed in blood, brain, cortex, tibial nerve, (Wntless) in Drosophila (P. Zhang, 2011). SNX3 is artery, thyroid, breast, ovary and testis required for the binding of VPS26 and VPS35 (genecards.org). association complex to endosomal membranes (M. Lucas, 2016). For efficient recruitment of retromer Protein proteins to the endosomes, SNX3 binding to PI3Ps of endosomes through its PX domain. RAB7A SNX3 belongs to Sorting Nexins family consisting GTPase is also recruited to the endosome. of more than 30 members (P.J. Cullen, 2008). SNX Consequently, VPS35, VPS26 and VPS29 trimer family members are classified according to their interacts with the endosome. SNX3 almost functions domain structures. Members of sorting nexins have as a bridge by interacting with the PI3Ps and the VPS a combination of the following domains: trimer. Binding of retromer to SNX3 causes a Bin/Rvs/Amphiphysin domain (BAR), Phox conformational change on retromer complex, which homology domain (PX), 4.1/Ezrin/Radixin/Moesin- creates a binding surface for cargo proteins (M. like domain (FERM), PXA (PX-associated domain Gallon, 2015). A), RGS (Regulator of G-protein signaling), PXC (PX- associated domain C) and MIT (microtubule- Homology interacting and trafficking molecule domain) (R.D. The SNX3 gene is conserved among species such as Teasdale, 2012). SNX3 has only the PX domain. chimpanzee, Rhesus monkey, dog, cow, mouse, rat, chicken, frog, zebrafish and yeast.(NCBI). Figure 3. SNX3 consists of only the PX domain. Atlas Genet Cytogenet Oncol Haematol. 2020; 24(8) 334 SNX3 (Sorting Nexin 3) Cicek E et al. accumulation in early endosomes (Chiow et al., Mutations 2012). A de novo reciprocal t(6;13)(q21;q12) translocation Acute Lymphoblastic Leukemia was detected in a patient with microcephaly, Dexamethasone (DEXA) is a frequently preferred microphthalmia, ectrodactyly, and prognathism chemotherapeutic drug for childhood acute (MMEP) and mental retardation. Gene mapping at lymphoblastic leukemia (ALL) patients, however, the site of the breakpoints showed that the drug resistance is a problem. Proteomic studies translocation breakpoint does not appear to disrupt revealed that SNX3 is expressed differentially any gene on chromosome 13, but does disrupt SNX3 between DEXA treated DEXA- resistant cell line gene on chromosome 6q21 (Ververoot et al., 2002). (REH) and non-DEXA treated REH. In REH cells, There are a mutations reported for SNX3 in bladder SNX3 expression is down-regulated. Additionally, urothelial carcinoma, breast invasive ductal both in high risk and standard risk group ALL carcinoma, breast invasive lobular carcinoma, colon patients, SNX3 downregulation is observed when adenocarcinoma, cutaneous melanoma, esophageal compared to normal control group. Downregulation squamous cell carcinoma, head and neck squamous of SNX3 may be associated with both cell carcinoma, lung squamous cell carcinoma, chemoresistance and tumorigenesis (Dehghan- papillary renal cell carcinoma, serous ovarian Nayeri et al., 2017). cancer, tubular stomach adenocarcinoma, uterine endometrioid carcinoma (cBioPortal database) Alzheimier Disease (Cerami et al., 2012; Gao et al., 2013). Neurotoxic amyloid β peptide (Aβ) with the processing of amyloid precursor protein ( APP) by Implicated in proteolytic cleavage has the leading role in SNX3 has been implicated in diverse diseases. Alzheimier disease (AD) pathogenesis (Vardarajan, 2012). Retromer complex including SNX3 provides Split Hand/Foot Malformation (SHFM) proper trafficking of APP, which is necessary to SNX3 locus has been implicated to be a possibly prevent abnormal production of Aβ peptide. It was important region for SHFM (Duijf et.al., 2003; reported that SNX3 has AD related SNPs. Braverman et.al., 1993; Gurrieri et.al., 1995; Correa- Overexpression of SNX3 in HEK293T showed Cerro et.al., 1996). 6q21 region is also associated reduction in the secreted Aβ level. Regulation of Aβ with some other malformations like microcephaly, peptide with controlling APP may make SNX3 a microphthalmia, ectrodactyly and prognathism candidate for AD treatment (Xu, 2018). (Duijf et. al., 2003 and Vervoort et.al., 2002). Parkinson's Disease MMEP (Microcephaly, Alpha-synuclein (SNCA) protein has a role in the microphthalmia, ectrodactyly and iron metabolism and expression. High expression prognathism) level of alpha-synuclein in dopaminergic neurons SNX3 disruption on 6q21 was reported in a patient causes Parkinson's disease. with MMEP and t(6;13)(q21;q12) but SNX3 In yeast, Fet3/Ftr1 complex has role in external iron mutations were not identified in other MMEP intake. When the external iron concentration is low, patients, which may suggest involvement of other interaction of Ftr1 C-terminus with Snx3-retromer genes (Vervoort et.al., 2002). complex provides retrograde transport of the complex. Under the condition of high external iron Autosomal Dominant Polycyctic concentration, internalized complex is degraded. Kidney Disease (ADPKD). Interestingly, action of the α-syn mimics the high Polycystin-1 (PKD1) and Polycystin-2 (PKD2) are iron concentration response and leads to degradation plasma membrane receptor-ion channel proteins of Fet3/Ftr1 via hindering the Snx3 interaction with implicated in ADPKD. SNX3 has a role in early endosome and hence, cellular iron homeostasis endocytosis of PKD2. It was reported that is disrupted (Patel, 2018). compounds that downregulate SNX3 expression or Anemia which inhibit its function could have therapeutic benefits for ADPKD patients. (Feng et al.,2017). SNX3 functions in the recycling of TFRC (transferrin receptor). Knockdown of snx3 in Epidermoid Carcinoma zebrafish embryos results in intensive anemia. SNX3 has a role in endosomal trafficking of TFRC
Load more

Recommended publications
  • Genome-Wide Screen Identifies Genes Whose Inactivation Confer Resistance to Cisplatin in Saccharomyces Cerevisiae
    Research Article Genome-Wide Screen Identifies Genes Whose Inactivation Confer Resistance to Cisplatin in Saccharomyces cerevisiae Ruea-Yea Huang, Martha Eddy, Marija Vujcic, and David Kowalski Department of Cancer Genetics, Roswell Park Cancer Institute, Buffalo, New York Abstract therapy (1). This may be due to the genomic instability of tumors, To identify novel genes that mediate cellular resistance to which gives rise to mutations or defects in multiple molecular cisplatin, we have screened the collection of Saccharomyces pathways. Both gain-of-function and loss-of-function mutations cerevisiae deletion strains. We have found reproducibly 22 can confer resistance to platinum compounds. The best known genes/open reading frames (ORF), which when deleted, confer examples are the loss of DNA mismatch repair (MMR) genes, resistance to cisplatin at a concentration that is lethal to wild- hMLH1, hMSH2, or hPMS2 (1, 4). MMR proteins function in type cells. Complementation of individual deletion strains recognition of damaged DNA adducts. Previous studies indicate with the corresponding wild-type gene abolished cisplatin that mutation or methylation-mediated silencing of these genes resistance, confirming that specific gene deletions caused the results in failure to recognize the adduct and propagate a signal to resistance. Twenty of the genes/ORFs identified have not been the apoptotic machinery, thereby producing low-level resistance to previously linked to cisplatin resistance and belong to several cisplatin (5). In addition, cisplatin treatment can enrich for malignant populations of cells that have lost DNA mismatch distinct functional groups. Major functional groups encode proteins involved in nucleotide metabolism, mRNA catabo- repair both in vitro and in vivo (4).
    [Show full text]
  • Molecular Mechanism for the Subversion of the Retromer Coat By
    Molecular mechanism for the subversion of the PNAS PLUS retromer coat by the Legionella effector RidL Miguel Romano-Morenoa, Adriana L. Rojasa, Chad D. Williamsonb, David C. Gershlickb, María Lucasa, Michail N. Isupovc, Juan S. Bonifacinob, Matthias P. Machnerd,1, and Aitor Hierroa,e,1 aStructural Biology Unit, Centro de Investigación Cooperativa en Biociencias, 48160 Derio, Spain; bCell Biology and Neurobiology Branch, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892; cThe Henry Wellcome Building for Biocatalysis, Biosciences, University of Exeter, Exeter EX4 4SB, United Kingdom; dDivision of Molecular and Cellular Biology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892; and eIKERBASQUE, Basque Foundation for Science, 48011 Bilbao, Spain Edited by Ralph R. Isberg, Howard Hughes Medical Institute and Tufts University School of Medicine, Boston, MA, and approved November 13, 2017 (received for review August 30, 2017) Microbial pathogens employ sophisticated virulence strategies to VAMP7 together with several Rab GTPases that function along cause infections in humans. The intracellular pathogen Legionella distinct trafficking pathways (18), and the Tre-2/Bub2/Cdc16 pneumophila encodes RidL to hijack the host scaffold protein domain family member 5 (TBC1D5), a GTPase-activating pro- VPS29, a component of retromer and retriever complexes critical for tein (GAP) that causes Rab7 inactivation and redistribution to endosomal cargo recycling. Here, we determined the crystal structure the cytosol (14). of L. pneumophila RidL in complex with the human VPS29–VPS35 Recent biochemical and structural characterization of single retromer subcomplex. A hairpin loop protruding from RidL inserts subunits and subcomplexes from retromer have provided insights into a conserved pocket on VPS29 that is also used by cellular ligands, into its modular architecture and mechanisms of action.
    [Show full text]
  • Mouse Vps29 Conditional Knockout Project (CRISPR/Cas9)
    https://www.alphaknockout.com Mouse Vps29 Conditional Knockout Project (CRISPR/Cas9) Objective: To create a Vps29 conditional knockout Mouse model (C57BL/6J) by CRISPR/Cas-mediated genome engineering. Strategy summary: The Vps29 gene (NCBI Reference Sequence: NM_019780 ; Ensembl: ENSMUSG00000029462 ) is located on Mouse chromosome 5. 4 exons are identified, with the ATG start codon in exon 1 and the TAA stop codon in exon 4 (Transcript: ENSMUST00000155671). Exon 2~3 will be selected as conditional knockout region (cKO region). Deletion of this region should result in the loss of function of the Mouse Vps29 gene. To engineer the targeting vector, homologous arms and cKO region will be generated by PCR using BAC clone RP23-97B19 as template. Cas9, gRNA and targeting vector will be co-injected into fertilized eggs for cKO Mouse production. The pups will be genotyped by PCR followed by sequencing analysis. Note: Exon 2 starts from about 0.73% of the coding region. The knockout of Exon 2~3 will result in frameshift of the gene. The size of intron 1 for 5'-loxP site insertion: 5536 bp, and the size of intron 3 for 3'-loxP site insertion: 533 bp. The size of effective cKO region: ~2760 bp. The cKO region does not have any other known gene. Page 1 of 8 https://www.alphaknockout.com Overview of the Targeting Strategy Wildtype allele 5' gRNA region gRNA region 3' 1 2 3 4 Targeting vector Targeted allele Constitutive KO allele (After Cre recombination) Legends Exon of mouse Vps29 Homology arm cKO region loxP site Page 2 of 8 https://www.alphaknockout.com Overview of the Dot Plot Window size: 10 bp Forward Reverse Complement Sequence 12 Note: The sequence of homologous arms and cKO region is aligned with itself to determine if there are tandem repeats.
    [Show full text]
  • VPS29 Exerts Opposing Effects on Endocytic Viral Entry 2 3 4 Daniel Poston1,2*, Yiska Weisblum1*, Alvaro Hobbs1, Paul D
    bioRxiv preprint doi: https://doi.org/10.1101/2021.08.06.455441; this version posted August 8, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY 4.0 International license. 1 VPS29 exerts opposing effects on endocytic viral entry 2 3 4 Daniel Poston1,2*, Yiska Weisblum1*, Alvaro Hobbs1, Paul D. Bieniasz1,3 5 6 7 1. Laboratory of Retrovirology, The Rockefeller University, 1230 York Avenue, New York NY 8 10065 9 2. Weill Cornell/Rockefeller/Sloan-Kettering Tri-Institutional MD-PhD Program, 1300 York 10 Avenue, New York NY 10021 11 3. Howard Hughes Medical Institute, The Rockefeller University, 1230 York Avenue, New 12 York NY 10065 13 14 15 *These authors contributed equally 16 17 18 Correspondence to: Paul D. Bieniasz, Laboratory of Retrovirology, The Rockefeller University, 19 31 1230 York Avenue, New York NY 10065 E.Mail [email protected] 20 21 22 23 SUMMARY 24 Emerging zoonotic viral pathogens threaten global health and there is an urgent need to discover 25 host and viral determinants influencing infection. We performed a loss-of-function genome-wide 26 CRISPR screen in a human lung cell line using HCoV-OC43, a human betacoronavirus. One 27 candidate gene, VPS29, was required for infection by HCoV-OC43, SARS-CoV-2, other 28 endemic and pandemic threat coronaviruses as well as ebolavirus. However, VPS29 deficiency 29 had no effect on certain other viruses that enter cells via endosomes and had an opposing, 30 enhancing effect on influenza A virus infection.
    [Show full text]
  • The P5-Atpase ATP13A1 Modulates MR1-Mediated Antigen Presentation
    bioRxiv preprint doi: https://doi.org/10.1101/2021.05.26.445708; this version posted May 27, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY 4.0 International license. The P5-ATPase ATP13A1 modulates MR1- mediated antigen presentation Corinna A. Kulicke1, Erica De Zan2, Zeynep Hein3, Claudia Gonzalez-Lopez1, Swapnil Ghanwat3, Natacha Veerapen4, Gurdyal S. Besra4, Paul Klenerman5,6, John C. Christianson7, Sebastian Springer3, Sebastian Nijman2, Vincenzo Cerundolo1, #, § , and Mariolina Salio1, # 1. MRC Human Immunology Unit, Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, UK 2. Ludwig Institute for Cancer Research Ltd. and Target Discovery Institute, Nuffield Department of Medicine, University of Oxford, Oxford, UK 3. Department of Life Sciences and Chemistry, Jacobs University, Bremen, Germany. 4. School of Biosciences, University of Birmingham, Birmingham B11 2TT, United Kingdom 5. Peter Medawar Building, Nuffield Department of Medicine, University of Oxford 6. Translational Gastroenterology Unit, Nuffield Department of Medicine, University of Oxford 7. Botnar Research Centre, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, UK # joint senior authors § deceased January 7th 2020 current addresses: C.K. – Pulmonary and Critical Care Medicine, Oregon Health and Science University, Portland, OR, United States; S.N. – Scenic Biotech BV, Amsterdam, The Netherlands correspondence: [email protected]; [email protected] Keywords: MHC I-related protein 1 (MR1), mucosal-associated invariant T cell (MAIT), MR1-restricted T cell (MR1T), antigen presentation, protein trafficking, HAP1, gene trap, ATP13A1, P5-type ATPase bioRxiv preprint doi: https://doi.org/10.1101/2021.05.26.445708; this version posted May 27, 2021.
    [Show full text]
  • Mathematical Model of Auxin Metabolism in Shoots Of
    RUSSIAN ACADEMY OF SCIENCES SIBERIAN BRANCH INSTITUTE OF CYTOLOGY AND GENETICS THE SIXTH INTERNATIONAL CONFERENCE ON BIOINFORMATICS OF GENOME REGULATION AND STRUCTURE Abstracts BGRS’2008 Novosibirsk, Russia June 22—28, 2008 Novosibirsk 2008 1 INTERNATIONAL PROGRAM COMMITTEE* Nikolay Kolchanov Institute of Cytology and Genetics SB RAS, Novosibirsk, Russia (Chairman of the Conference) Ralf Hofestadt University of Bielefeld, Germany (Co-Chairman of the Conference) Dagmara Furman Institute of Cytology and Genetics SB RAS, Novosibirsk, (Conference Scientific Secretary) Dmitry Afonnikov Institute of Cytology and Genetics SB RAS, Novosibirsk, Russia Shandar Ahmad National Institute of Biomedical Innovation, Japan Philip Bourne University of California San Diego, San-Diego, USA Samir Brahmachari Institute of Genomics and Integrative Biology, Delhi, India Ming Chen Department of Bioinformatics Zhejiang University, Hangzhou, China А. Fazel Famili University of Ottawa, IIT/ITI - National Research Council Canada, Ottawa, Canada Mikhail Gelfand Institute for Information Transmission Problems RAS, Russia Boris M. Glinsky Institute of Computational Mathematics and Mathematical Geophysics SB RAS, Novosibirsk, Russia Nikolay Goncharov Institute of Cytology and Genetics, Novosibirsk, Russia Charlie Hodgman Multidisciplinary Centre for Integrative Biology, School of Biosciences, University of Nottingham, UK Alexis Ivanov Institute of Biomedical Chemistry RAMS, Moscow, Russia Manfred Kayser Erasmus University Medical Centre Rotterdam, Rotterdam, The Netherlands
    [Show full text]
  • COMMD1 Is Linked to the WASH Complex and Regulates Endosomal Trafficking of the Copper Transporter ATP7A
    M BoC | ARTICLE COMMD1 is linked to the WASH complex and regulates endosomal trafficking of the copper transporter ATP7A Christine A. Phillips-Krawczaka,*, Amika Singlab,*, Petro Starokadomskyyb, Zhihui Denga,c, Douglas G. Osbornea, Haiying Lib, Christopher J. Dicka, Timothy S. Gomeza, Megan Koeneckeb, Jin-San Zhanga,d, Haiming Daie, Luis F. Sifuentes-Dominguezb, Linda N. Gengb, Scott H. Kaufmanne, Marco Y. Heinf, Mathew Wallisg, Julie McGaughrang,h, Jozef Geczi,j, Bart van de Sluisk, Daniel D. Billadeaua,l, and Ezra Bursteinb,m aDepartment of Immunology, eDepartment of Molecular Pharmacology and Experimental Therapeutics, and lDepartment of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, Mayo Clinic, Rochester, MN 55905; bDepartment of Internal Medicine and mDepartment of Molecular Biology, UT Southwestern Medical Center, Dallas, TX 75390-9151; cDepartment of Pathophysiology, Qiqihar Medical University, Qiqihar, Heilongjiang 161006, China; dSchool of Pharmaceutical Sciences and Key Laboratory of Biotechnology and Pharmaceutical Engineering, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China; fMax Planck Institute of Biochemistry, 82152 Martinsried, Germany; gGenetic Health Queensland at the Royal Brisbane and Women’s Hospital, Herston, Queensland 4029, Australia; hSchool of Medicine, University of Queensland, Brisbane, Queensland 4072, Australia; iRobinson Institute and jDepartment of Paediatrics, University of Adelaide, Adelaide, South Australia 5005, Australia; kSection of Molecular Genetics at the Department of Pediatrics, University Medical Center Groningen, University of Groningen, 9713 Groningen, Netherlands ABSTRACT COMMD1 deficiency results in defective copper homeostasis, but the mecha- Monitoring Editor nism for this has remained elusive. Here we report that COMMD1 is directly linked to early Jean E. Gruenberg endosomes through its interaction with a protein complex containing CCDC22, CCDC93, and University of Geneva C16orf62.
    [Show full text]
  • And Post-Synaptic Abnormalities in Schizophrenia Lynsey S
    bioRxiv preprint doi: https://doi.org/10.1101/384560; this version posted August 3, 2018. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC 4.0 International license. A Transcriptome Wide Association Study implicates specific pre- and post-synaptic abnormalities in Schizophrenia Lynsey S Hall (PhD)1*, Christopher W Medway (PhD)1*, Antonio F Pardinas (PhD)1, Elliott G Rees (PhD)1, Valentina Escott-Price (PhD)1, Andrew Pocklington (PhD)1, Peter A Holmans (PhD)1, James TR Walters (MRCPsych, PhD)1, Michael J Owen (FRCPsych, PhD)1, Michael C O’Donovan (FRCPsych, PhD)1 *joint first author 1. MRC Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, Cardiff, UK Corresponding author: Dr Lynsey Hall MRC Centre for Neuropsychiatric Genetics and Genomics Cardiff University Hadyn Ellis Building Cardiff CF24 4HQ Phone: +44 (0)29 2068 8422 Email: [email protected] bioRxiv preprint doi: https://doi.org/10.1101/384560; this version posted August 3, 2018. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC 4.0 International license. Abstract Schizophrenia is a complex highly heritable disorder. Genome-wide association studies have identified multiple loci that influence the risk of developing schizophrenia, although the causal variants driving these associations and their impacts on specific genes are largely unknown.
    [Show full text]
  • Deconvoluting Cell-Type Specific 3'UTR Isoform Expression in the Adult and Developing Cerebellum Saša Jereb
    Rockefeller University Digital Commons @ RU Student Theses and Dissertations 2017 Deconvoluting Cell-Type Specific 3'UTR Isoform Expression in the Adult and Developing Cerebellum Saša Jereb Follow this and additional works at: http://digitalcommons.rockefeller.edu/ student_theses_and_dissertations Part of the Life Sciences Commons Recommended Citation Jereb, Saša, "Deconvoluting Cell-Type Specific 3'UTR Isoform Expression in the Adult and Developing Cerebellum" (2017). Student Theses and Dissertations. 394. http://digitalcommons.rockefeller.edu/student_theses_and_dissertations/394 This Thesis is brought to you for free and open access by Digital Commons @ RU. It has been accepted for inclusion in Student Theses and Dissertations by an authorized administrator of Digital Commons @ RU. For more information, please contact [email protected]. DECONVOLUTING CELL-TYPE SPECIFIC 3’UTR ISOFORM EXPRESSION IN THE ADULT AND DEVELOPING CEREBELLUM A Thesis Presented to the Faculty of The Rockefeller University in Partial Fulfillment of the Requirements for the degree of Doctor of Philosophy by Saša Jereb June 2017 © Copyright by Saša Jereb 2017 DECONVOLUTING CELL-TYPE SPECIFIC 3’UTR ISOFORM EXPRESSION IN THE ADULT AND DEVELOPING CEREBELLUM Saša Jereb, Ph.D. The Rockefeller University 2017 Alternative polyadenylation has been implicated in the regulation of mRNA translation and stability, as well as mRNA and protein localization. However, it is unclear to what extent alternative polyadenylation regulates these processes uniquely in specific cell types. Using a newly developed technique, termed conditionally-tagged poly(A) binding protein-mediated mRNA 3’ end retrieval by crosslinking immunoprecipitation (cTag-PAPERCLIP), we discovered significant differences in alternative polyadenylation between granule and Purkinje cells in the mouse cerebellum, as well as between proliferating and adult granule cells.
    [Show full text]
  • Combined Proteomic and Metabolomic Profiling of The
    Combined Proteomic and Metabolomic Profiling of the Arabidopsis thaliana vps29 Mutant Reveals Pleiotropic Functions of the Retromer in Seed Development Thomas Durand, Gwendal Cueff, Béatrice Godin, Benoît Valot, Gilles Clément, Thierry Gaude, Loïc Rajjou To cite this version: Thomas Durand, Gwendal Cueff, Béatrice Godin, Benoît Valot, Gilles Clément, et al.. Combined Proteomic and Metabolomic Profiling of the Arabidopsis thaliana vps29 Mutant Reveals Pleiotropic Functions of the Retromer in Seed Development. International Journal of Molecular Sciences, MDPI, 2019, 20 (2), pp.362. 10.3390/ijms20020362. hal-02401707 HAL Id: hal-02401707 https://hal.archives-ouvertes.fr/hal-02401707 Submitted on 26 May 2020 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. Distributed under a Creative Commons Attribution| 4.0 International License International Journal of Molecular Sciences Article Combined Proteomic and Metabolomic Profiling of the Arabidopsis thaliana vps29 Mutant Reveals Pleiotropic Functions of the Retromer in Seed Development 1, 2 2 3, 2 Thomas C Durand y, Gwendal Cueff ,Béatrice Godin , Benoît Valot z, Gilles Clément , Thierry Gaude 1,* and Loïc Rajjou 2,* 1 Laboratoire Reproduction et Développement des Plantes, Université de Lyon, ENS de Lyon, UCB Lyon I, CNRS, INRA, 69342 Lyon, France; [email protected] 2 Institut Jean-Pierre Bourgin, INRA, AgroParisTech, CNRS, Université Paris-Saclay, 78000 Versailles cedex, France; gwendal.cueff@inra.fr (G.C.); [email protected] (B.G.); [email protected] (G.C.) 3 GQE - Le Moulon, INRA, Univ.
    [Show full text]
  • Retromer Deficiency in Amyotrophic Lateral Sclerosis
    Retromer deficiency in amyotrophic lateral sclerosis Eduardo J Pérez-Torres Submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy under the Executive Committee of the Graduate School of Arts and Sciences COLUMBIA UNIVERSITY 2020 © 2020 Eduardo J Pérez-Torres All Rights Reserved ABSTRACT RETROMER DEFICIENCY IN AMYOTROPHIC LATERAL SCLEROSIS Eduardo J Pérez-Torres The retromer is a protein complex whose function is to mediate the recycling of proteins from the endosome to either the plasma membrane or the trans-Golgi network. A deficit in retromer function has been associated with multiple neurodegenerative disorders, including Alzheimer’s disease (AD) and Parkinson’s disease (PD). In both AD and PD, deficiencies have been found in retromer expression both in patient tissues and in animal models of disease. Furthermore, mutations in the retromer and in retromer-associated genes have been strongly linked with both diseases. Despite ample evidence of the link between the retromer and neurodegeneration, little is known about the retromer in the context of amyotrophic lateral sclerosis (ALS), another common neurodegenerative disorder. ALS is an adult-onset neurodegenerative disorder of the upper and lower motor neurons (MNs) characterized by muscle wasting and weakness leading to death within 3-5 years after diagnosis. To date, the most commonly used model of ALS is a transgenic (Tg) mouse that overexpresses an ALS-causing G93A mutation in the human superoxide dismutase 1 (SOD1) gene. In this study, I first establish a link between the retromer and ALS by showing that cells from ALS patients as well as tissues and cells from SOD1G93A-Tg mice express lower protein levels of the retromer core components—vacuolar protein sorting 35 (Vps35), Vps26a, and Vps29.
    [Show full text]
  • ESRP2 Controls an Adult Splicing Programme in Hepatocytes to Support Postnatal Liver Maturation
    ARTICLE Received 3 May 2015 | Accepted 25 Sep 2015 | Published 4 Nov 2015 DOI: 10.1038/ncomms9768 OPEN ESRP2 controls an adult splicing programme in hepatocytes to support postnatal liver maturation Amruta Bhate1,*, Darren J. Parker1,*, Thomas W. Bebee2, Jaegyoon Ahn3, Waqar Arif1, Edrees H. Rashan1, Sandip Chorghade1, Anthony Chau1, Jae-Hyung Lee2, Sayeepriyadarshini Anakk4, Russ P. Carstens2, Xinshu Xiao3 & Auinash Kalsotra1,5 Although major genetic networks controlling early liver specification and morphogenesis are known, the mechanisms responsible for postnatal hepatic maturation are poorly understood. Here we employ global analyses of the mouse liver transcriptome to demonstrate that postnatal remodelling of the liver is accompanied by large-scale transcriptional and post- transcriptional transitions that are cell-type-specific and temporally coordinated. Combining detailed expression analyses with gain- and loss-of-function studies, we identify epithelial splicing regulatory protein 2 (ESRP2) as a conserved regulatory factor that controls the neonatal-to-adult switch of B20% of splice isoforms in mouse and human hepatocytes. The normal shift in splicing coincides tightly with dramatic postnatal induction of ESRP2 in hepatocytes. We further demonstrate that forced expression of ESRP2 in immature mouse and human hepatocytes is sufficient to drive a reciprocal shift in splicing and causes various physiological abnormalities. These findings define a direct role for ESRP2 in the generation of conserved repertoires of adult splice isoforms that facilitate terminal differentiation and maturation of hepatocytes. 1 Department of Biochemistry and Medical Biochemistry, University of Illinois, Champaign, Illinois 61801, USA. 2 Departments of Medicine and Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
    [Show full text]