DOCSLIB.ORG

THE ROLE of PARD3 in SCHWANN CELL DEVELOPMENT By

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
THE ROLE of PARD3 in SCHWANN CELL DEVELOPMENT By THE ROLE OF PARD3 IN SCHWANN CELL DEVELOPMENT by ALEXANDER JAMES BLASKY B.S., St. Norbert College, 2004 A thesis submitted to the Faculty of the Graduate School of the University of Colorado in partial fulfillment of the requirements for the degree of Doctor of Philosophy Cell Biology, Stem Cells and Development Program 2014 This thesis for the Doctor of Philosophy degree by Alexander James Blasky has been approved for the Cell Biology, Stem Cells and Development Program by Thomas Finger, Chair Angela Ribera Chad Pearson Rytis Prekeris John Sladek Bruce Appel, Advisor Date 05/02/14 ii Blasky, Alexander James (Ph.D., Cell Biology, Stem Cells and Development) The Role of Pard3 in Schwann Cell Development Thesis directed by Professor Bruce Appel ABSTRACT Schwann cells are the myelin forming glial of the peripheral nervous system and are required for the rapid transmission of sensory and motor information between the central nervous system and the peripheral tissues. During development, the cells fated to become myelinating Schwann cells undergo a stepwise sequence of events including delamination from the neuroepithelium, directed migration into peripheral tissue, axon ensheathment and synthesis of myelin membrane. How Schwann cells regulate the transitions between these distinct behaviors is unclear. These dynamic developmental steps require cell polarity and therefore imply dynamic functions of proteins that contribute to cell polarity. However, few studies have investigated the role of any polarity proteins during the entire Schwann cell progression in vivo. In this work investigate the role of Par complex protein Pard3 in regulating polarity necessary for directed migration, axon ensheathment and myelination by Schwann cells. Time-lapse imaging revealed that neural crest delamination was normal but that migrating cells were disorganized with substantial amounts of overlapping membrane. Nevertheless, neural crest cells migrated to appropriate peripheral targets. Schwann cells wrapped motor axons and, although myelin gene expression was delayed, myelination proceeded to completion. iii Pard3 mediates contact inhibition between neural crest cells and promotes timely myelin gene expression but is not essential for neural crest migration or myelination. The form and content of this abstract are approved. I recommend its publication. Approved: Bruce Appel iv To Casey, for your patience, your laughter, and your love. v TABLE OF CONTENTS CHAPTER I. SCHWANN CELLS AND CELL POLARITY .................................... 1 Abstract .................................................................................................... 1 Schwann Cell Development ..................................................................... 2 Schwann Cell Stages ........................................................................... 2 Cell Polarity during Schwann Cell Behaviors .................................... 6 Neural Crest Cells and Schwann Cell Development ........................ 15 Directed Cell Migration .................................................................... 16 Zebrafish as a Model System for Schwann Cell Development ........ 19 Schwann Cell Behaviors ........................................................................ 20 Delamination from the Neuroepithelial Tissue .............................. 20 Migration to Peripheral Targets ....................................................... 23 Schwann Cell Myelination ............................................................... 30 Disease .................................................................................................... 35 Aim and Structure .................................................................................. 35 Aim .................................................................................................... 35 Structure .......................................................................................... 36 II. PARD3 REGULATES CONTACT BETWEEN NEURAL CREST CELLS AND THE TIMING OF SCHWANN CELL DIFFERENTIATION BUT IS NOT ESSENTIAL FOR NEURAL CREST MIGRATION OR MYELINATION .................. 37 Abstract .................................................................................................. 37 Introduction .......................................................................................... 38 Results ................................................................................................... 40 vi Neural Crest Delamination from the Neuroepithelium Proceeds Normally in the Absence of pard3 Function ................... 40 Pard3 Promotes Contact Mediated Inhibition but Does Not Drive Neural Crest Cell Migration .................................................. 46 pard3 Mutant Schwann Cells Myelinate Motor Axons ................... 53 Discussion .............................................................................................. 54 Experimental Procedures ..................................................................... 62 III. PAR COMPLEX PROTEINS IN SCHWANN CELL DEVELOPMENT ................................................................................ 66 Introduction .......................................................................................... 66 Results ................................................................................................... 68 Schwann Cells Express mbp in Par Complex Mutants ................... 68 Motor Neuron Morphology Unchanged in Pard3 Mutants ............ 69 miR-219 and Jaw Formation in Pard3 Mutants. ............................. 71 (PH)AKT-GF Enriched at Migratory Cell Leading Edge. ................ 74 Pard3-GFP is Enriched in Neuroepithelial Cell Apical Domains In Vivo. .............................................................................. 76 Discussion .............................................................................................. 78 IV. DISCUSSION AND FUTURE DIRECTIONS ................................ 81 Summary ................................................................................................ 81 Future Directions ................................................................................... 87 REFERENCES ............................................................................................... 90 vii LIST OF FIGURES FIGURES 1.1. Stages of Schwann Cell Development ........................................................... 3 1.2. Epithelial Cell Polarity Proteins during Delamination. ............................... 8 1.3. Alignment of Zebrafish Pard3 with Known Pard3 Homologs .................... 11 1.4. Schematic Representation of Pard3 ............................................................ 12 1.5. Comparison of Zebrafish Pard3 with Known Par3 Homologs. .................. 13 1.6. Directed Cell Migration. .............................................................................. 18 1.7. Collective Cell Migration. ........................................................................... 26 1.8. Contact Inhibition of Locomotion During Cell Migration. ......................... 27 2.1. Characterization of Maternal and Zygotic pard3 Functions. .................... 42 2.2. Schwann Cells Exit the Dorsal Neural Tube on Schedule in pard3 Mutants. ....................................................................................................... 45 2.3. pard3 is Not Essential for Neural Crest Migration. .................................... 47 2.4. Pard3 Mediates Contact Inhibition between Neural Crest Cells. .............. 50 2.5. Pard3 Localizes at Transient Points of Contact Between Neural Crest Cells. ................................................................................................... 52 2.6. Schwann Cells Wrap Motor Axons but Delay mbp Expression in the Absence of pard3 Function. ........................................................................ 56 2.7. pard3 is Not Essential for Schwann Cell Myelination. .............................. 58 3.1. Schwann Cells Delay mbp Expression in the Absence of pard3 Function. ..................................................................................................... 70 viii 3.2. Motor Neuron Specification and Branching Appear Normal in the Absence of pard3 Function. ........................................................................ 72 3.3. Knockdown of mir-219 Disrupts Jaw Formation. ...................................... 73 3.4 PIP3 Activation is Enriched at the Migratory Leading Edge and Sites of Cell-Cell Contact. ............................................................................ 75 3.5. Pard3-GFP is Localized along Neuroepithelial Cell Apical Domains In Vivo. ......................................................................................................... 77 ix CHAPTER I SCHWANN CELLS AND CELL POLARITY Abstract Schwann cells are the myelin forming glial cells of the peripheral nervous system. The origin and development of the Schwann cell has been well characterized and their development has been divided into a series of maturation stages. The cells fated to become myelinating Schwann cells undergo a stepwise sequence of events including delamination from the neuroepithelium, directed migration into peripheral tissue, axon ensheathment and synthesis of myelin membrane. How Schwann cells regulate the transitions between these distinct behaviors is unclear. At each stage of their development Schwann cells are polarized, implying important roles for molecules that create cellular asymmetries.
Load more

Recommended publications
  • Transcriptome Analyses of Rhesus Monkey Pre-Implantation Embryos Reveal A
    Downloaded from genome.cshlp.org on September 23, 2021 - Published by Cold Spring Harbor Laboratory Press Transcriptome analyses of rhesus monkey pre-implantation embryos reveal a reduced capacity for DNA double strand break (DSB) repair in primate oocytes and early embryos Xinyi Wang 1,3,4,5*, Denghui Liu 2,4*, Dajian He 1,3,4,5, Shengbao Suo 2,4, Xian Xia 2,4, Xiechao He1,3,6, Jing-Dong J. Han2#, Ping Zheng1,3,6# Running title: reduced DNA DSB repair in monkey early embryos Affiliations: 1 State Key Laboratory of Genetic Resources and Evolution, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan 650223, China 2 Key Laboratory of Computational Biology, CAS Center for Excellence in Molecular Cell Science, Collaborative Innovation Center for Genetics and Developmental Biology, Chinese Academy of Sciences-Max Planck Partner Institute for Computational Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China 3 Yunnan Key Laboratory of Animal Reproduction, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan 650223, China 4 University of Chinese Academy of Sciences, Beijing, China 5 Kunming College of Life Science, University of Chinese Academy of Sciences, Kunming, Yunnan 650204, China 6 Primate Research Center, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, 650223, China * Xinyi Wang and Denghui Liu contributed equally to this work 1 Downloaded from genome.cshlp.org on September 23, 2021 - Published by Cold Spring Harbor Laboratory Press # Correspondence: Jing-Dong J. Han, Email: [email protected]; Ping Zheng, Email: [email protected] Key words: rhesus monkey, pre-implantation embryo, DNA damage 2 Downloaded from genome.cshlp.org on September 23, 2021 - Published by Cold Spring Harbor Laboratory Press ABSTRACT Pre-implantation embryogenesis encompasses several critical events including genome reprogramming, zygotic genome activation (ZGA) and cell fate commitment.
    [Show full text]
  • Orally Administered Glucosylceramide Improves the Skin Barrier Function by Upregulating Genes Associated with the Tight Junction and Cornified Envelope Formation
    110215 (251) Biosci. Biotechnol. Biochem., 75 (8), 110215-1–8, 2011 Orally Administered Glucosylceramide Improves the Skin Barrier Function by Upregulating Genes Associated with the Tight Junction and Cornified Envelope Formation y Ritsuro IDETA, Tomohiro SAKUTA, Yusuke NAKANO, and Taro UCHIYAMA Shiseido Functional Food Research and Development Center, 2-12-1 Fukuura, Kanazawa-ku, Yokohama 236-8643, Japan Received March 18, 2011; Accepted May 9, 2011; Online Publication, August 7, 2011 [doi:10.1271/bbb.110215] Dietary glucosylceramide improves the skin barrier mammalian skin barrier function through their role as function. We used a microarray system to analyze the intracellular lipids.6) The skin barrier is essential for mRNA expression in SDS-treated dorsal skin of the protecting against physical stimuli, thermal challenge, hairless mouse to elucidate the molecular mechanisms ultraviolet light (UV), chemical substances and micro- involved. The transepidermal water loss of mouse skin organisms, as well as for preventing water loss.7) The was increased by the SDS treatment, this increase being barrier function is mainly localized in the stratum significantly reduced by a prior oral administration of corneum (SC) which is formed in the outermost layer of glucosylceramides. The microarray-evaluated mRNA the epidermis and consists of the cornified envelope expressionAdvance ratio showed a statistically significant View in- (CE) and intercellular multilamellar lipids. CE forms crease in the expression of genes related to the cornified a highly durable and flexible barrier8) comprising a envelope and tight junction formation when compared 15-nm-thick structure composed of such insoluble with all genes in the glucosylceramide-fed/SDS-treated proteins as involucrin, loricrin, and small proline-rich mouse skin.
    [Show full text]
  • Supplementary Table 1: Adhesion Genes Data Set
    Supplementary Table 1: Adhesion genes data set PROBE Entrez Gene ID Celera Gene ID Gene_Symbol Gene_Name 160832 1 hCG201364.3 A1BG alpha-1-B glycoprotein 223658 1 hCG201364.3 A1BG alpha-1-B glycoprotein 212988 102 hCG40040.3 ADAM10 ADAM metallopeptidase domain 10 133411 4185 hCG28232.2 ADAM11 ADAM metallopeptidase domain 11 110695 8038 hCG40937.4 ADAM12 ADAM metallopeptidase domain 12 (meltrin alpha) 195222 8038 hCG40937.4 ADAM12 ADAM metallopeptidase domain 12 (meltrin alpha) 165344 8751 hCG20021.3 ADAM15 ADAM metallopeptidase domain 15 (metargidin) 189065 6868 null ADAM17 ADAM metallopeptidase domain 17 (tumor necrosis factor, alpha, converting enzyme) 108119 8728 hCG15398.4 ADAM19 ADAM metallopeptidase domain 19 (meltrin beta) 117763 8748 hCG20675.3 ADAM20 ADAM metallopeptidase domain 20 126448 8747 hCG1785634.2 ADAM21 ADAM metallopeptidase domain 21 208981 8747 hCG1785634.2|hCG2042897 ADAM21 ADAM metallopeptidase domain 21 180903 53616 hCG17212.4 ADAM22 ADAM metallopeptidase domain 22 177272 8745 hCG1811623.1 ADAM23 ADAM metallopeptidase domain 23 102384 10863 hCG1818505.1 ADAM28 ADAM metallopeptidase domain 28 119968 11086 hCG1786734.2 ADAM29 ADAM metallopeptidase domain 29 205542 11085 hCG1997196.1 ADAM30 ADAM metallopeptidase domain 30 148417 80332 hCG39255.4 ADAM33 ADAM metallopeptidase domain 33 140492 8756 hCG1789002.2 ADAM7 ADAM metallopeptidase domain 7 122603 101 hCG1816947.1 ADAM8 ADAM metallopeptidase domain 8 183965 8754 hCG1996391 ADAM9 ADAM metallopeptidase domain 9 (meltrin gamma) 129974 27299 hCG15447.3 ADAMDEC1 ADAM-like,
    [Show full text]
  • High Expression of PARD3 Predicts Poor Prognosis in Hepatocellular Carcinoma Songwei Li1, Jian Huang2, Fan Yang1, Haiping Zeng3, Yuyun Tong1 & Kejia Li2*
    www.nature.com/scientificreports OPEN High expression of PARD3 predicts poor prognosis in hepatocellular carcinoma Songwei Li1, Jian Huang2, Fan Yang1, Haiping Zeng3, Yuyun Tong1 & Kejia Li2* Hepatocellular carcinoma (HCC) is one of the most commonly cancers with poor prognosis and drug response. Identifying accurate therapeutic targets would facilitate precision treatment and prolong survival for HCC. In this study, we analyzed liver hepatocellular carcinoma (LIHC) RNA sequencing (RNA-seq) data from The Cancer Genome Atlas (TCGA), and identifed PARD3 as one of the most signifcantly diferentially expressed genes (DEGs). Then, we investigated the relationship between PARD3 and outcomes of HCC, and assessed predictive capacity. Moreover, we performed functional enrichment and immune infltration analysis to evaluate functional networks related to PARD3 in HCC and explore its role in tumor immunity. PARD3 expression levels in 371 HCC tissues were dramatically higher than those in 50 paired adjacent liver tissues (p < 0.001). High PARD3 expression was associated with poor clinicopathologic feathers, such as advanced pathologic stage (p = 0.002), vascular invasion (p = 0.012) and TP53 mutation (p = 0.009). Elevated PARD3 expression also correlated with lower overall survival (OS, HR = 2.08, 95% CI = 1.45–2.98, p < 0.001) and disease-specifc survival (DSS, HR = 2.00, 95% CI = 1.27–3.16, p = 0.003). 242 up-regulated and 71 down-regulated genes showed signifcant association with PARD3 expression, which were involved in genomic instability, response to metal ions, and metabolisms. PARD3 is involved in diverse immune infltration levels in HCC, especially negatively related to dendritic cells (DCs), cytotoxic cells, and plasmacytoid dendritic cells (pDCs).
    [Show full text]
  • Human Induced Pluripotent Stem Cell–Derived Podocytes Mature Into Vascularized Glomeruli Upon Experimental Transplantation
    BASIC RESEARCH www.jasn.org Human Induced Pluripotent Stem Cell–Derived Podocytes Mature into Vascularized Glomeruli upon Experimental Transplantation † Sazia Sharmin,* Atsuhiro Taguchi,* Yusuke Kaku,* Yasuhiro Yoshimura,* Tomoko Ohmori,* ‡ † ‡ Tetsushi Sakuma, Masashi Mukoyama, Takashi Yamamoto, Hidetake Kurihara,§ and | Ryuichi Nishinakamura* *Department of Kidney Development, Institute of Molecular Embryology and Genetics, and †Department of Nephrology, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan; ‡Department of Mathematical and Life Sciences, Graduate School of Science, Hiroshima University, Hiroshima, Japan; §Division of Anatomy, Juntendo University School of Medicine, Tokyo, Japan; and |Japan Science and Technology Agency, CREST, Kumamoto, Japan ABSTRACT Glomerular podocytes express proteins, such as nephrin, that constitute the slit diaphragm, thereby contributing to the filtration process in the kidney. Glomerular development has been analyzed mainly in mice, whereas analysis of human kidney development has been minimal because of limited access to embryonic kidneys. We previously reported the induction of three-dimensional primordial glomeruli from human induced pluripotent stem (iPS) cells. Here, using transcription activator–like effector nuclease-mediated homologous recombination, we generated human iPS cell lines that express green fluorescent protein (GFP) in the NPHS1 locus, which encodes nephrin, and we show that GFP expression facilitated accurate visualization of nephrin-positive podocyte formation in
    [Show full text]
  • Association Study Between Polymorphisms of the PARD3 Gene and Schizophrenia
    EXPERIMENTAL AND THERAPEUTIC MEDICINE 3: 881-885, 2012 Association study between polymorphisms of the PARD3 gene and schizophrenia SU KANG KIM1*, JONG YOON LEE2*, HAE JEONG PARK1, JONG WOO KIM3 and JOO-HO CHUNG1 1Department of Pharmacology and Kohwang Medical Research Institute; 2School of Medicine, Kyung Hee University, Seoul 130-701; 3Department of Neuropsychiatry, School of Medicine, Kyung Hee University, Seoul 130-702, Republic of Korea Received December 13, 2011; Accepted January 20, 2012 DOI: 10.3892/etm.2012.496 Abstract. The aim of this study was to investigate whether Introduction par-3 partitioning defective 3 homolog (C. elegans) (PARD3) single nucleotide polymorphisms (SNPs) are associated with Schizophrenia is a severe, debilitating, psychiatric disorder. schizophrenia. A total of 204 Korean schizophrenic patients Although the exact etiology of schizophrenia is unknown, [117 male, 41.1±9.6 years (mean age ± SD); 87 female, twin, family and adoption studies have provided consistent 42.6±11.5] and 351 control subjects (170 male, 43.8±6.6 years; evidence that genetic factors play a major role in the pathogen- 181 female, 44.2±5.8) were enrolled. We genotyped nine esis of schizophrenia. SNPs of the PARD3 gene [rs7075263 (intron), rs10827392 In a recent study, the data showed that polymorphisms (intron), rs773970 (intron), rs2252655 (intron), rs10763984 of several genes affect gene expression or the function of (intron), rs3781128 (Ser889Ser), rs1936429 (intron), rs671228 the encoded protein in the human brain (1). Clinical, epide- (intron) and rs16935163 (intron)]. Genotypes of PARD3 poly- miological, neuroimaging and postmortem data suggest that morphisms were evaluated by direct sequencing.
    [Show full text]
  • ADHD) Gene Networks in Children of Both African American and European American Ancestry
    G C A T T A C G G C A T genes Article Rare Recurrent Variants in Noncoding Regions Impact Attention-Deficit Hyperactivity Disorder (ADHD) Gene Networks in Children of both African American and European American Ancestry Yichuan Liu 1 , Xiao Chang 1, Hui-Qi Qu 1 , Lifeng Tian 1 , Joseph Glessner 1, Jingchun Qu 1, Dong Li 1, Haijun Qiu 1, Patrick Sleiman 1,2 and Hakon Hakonarson 1,2,3,* 1 Center for Applied Genomics, Children’s Hospital of Philadelphia, Philadelphia, PA 19104, USA; [email protected] (Y.L.); [email protected] (X.C.); [email protected] (H.-Q.Q.); [email protected] (L.T.); [email protected] (J.G.); [email protected] (J.Q.); [email protected] (D.L.); [email protected] (H.Q.); [email protected] (P.S.) 2 Division of Human Genetics, Department of Pediatrics, The Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA 3 Department of Human Genetics, Children’s Hospital of Philadelphia, Philadelphia, PA 19104, USA * Correspondence: [email protected]; Tel.: +1-267-426-0088 Abstract: Attention-deficit hyperactivity disorder (ADHD) is a neurodevelopmental disorder with poorly understood molecular mechanisms that results in significant impairment in children. In this study, we sought to assess the role of rare recurrent variants in non-European populations and outside of coding regions. We generated whole genome sequence (WGS) data on 875 individuals, Citation: Liu, Y.; Chang, X.; Qu, including 205 ADHD cases and 670 non-ADHD controls. The cases included 116 African Americans H.-Q.; Tian, L.; Glessner, J.; Qu, J.; Li, (AA) and 89 European Americans (EA), and the controls included 408 AA and 262 EA.
    [Show full text]
  • Role of PDZ-Binding Motif from West Nile Virus NS5 Protein on Viral
    www.nature.com/scientificreports OPEN Role of PDZ‑binding motif from West Nile virus NS5 protein on viral replication Emilie Giraud1*, Chloé Otero del Val2, Célia Caillet‑Saguy2, Nada Zehrouni2, Cécile Khou5, Joël Caillet4, Yves Jacob3, Nathalie Pardigon5 & Nicolas Wolf2 West Nile virus (WNV) is a Flavivirus, which can cause febrile illness in humans that may progress to encephalitis. Like any other obligate intracellular pathogens, Flaviviruses hijack cellular protein functions as a strategy for sustaining their life cycle. Many cellular proteins display globular domain known as PDZ domain that interacts with PDZ‑Binding Motifs (PBM) identifed in many viral proteins. Thus, cellular PDZ‑containing proteins are common targets during viral infection. The non‑structural protein 5 (NS5) from WNV provides both RNA cap methyltransferase and RNA polymerase activities and is involved in viral replication but its interactions with host proteins remain poorly known. In this study, we demonstrate that the C‑terminal PBM of WNV NS5 recognizes several human PDZ‑ containing proteins using both in vitro and in cellulo high‑throughput methods. Furthermore, we constructed and assayed in cell culture WNV replicons where the PBM within NS5 was mutated. Our results demonstrate that the PBM of WNV NS5 is important in WNV replication. Moreover, we show that knockdown of the PDZ‑containing proteins TJP1, PARD3, ARHGAP21 or SHANK2 results in the decrease of WNV replication in cells. Altogether, our data reveal that interactions between the PBM of NS5 and PDZ‑containing proteins afect West Nile virus replication. Arboviruses include numerous human and animal pathogens that are important global health threats responsible for arboviroses.
    [Show full text]
  • Itga4 Cldn16 Cldn9 Cldn15 Cldn22 Ocln Esam
    Supplementary material J Med Genet Table S1. List of 263 genes included in the AGS-LEUK panel. Axonal Guidance Signaling genes as AGS and Leukocyte transvasation genes as LEUK. List of genes (AGS) List of genes (LEUK) ABLIM1 CLDN11 ACTR3 MMP14 ADAM11 MMP15 ADAM23 CTNNA1 ADAMTS1 ENSG00000130396 ADAMTS4 CLDN6 ADAMTS9 MMP24 ARHGEF15 ARHGAP12 ARHGEF6 DLC1 ARPC1B TIMP2 BDNF RAPGEF3 BMP1 F11R BMP4 CLDN23 BMP6 CLDN8 BMP7 JAM3 CXCL12 CLDN3 CXCR4 ARHGAP8 DPYSL5 ICAM1 EFNA1 MMP16 EFNA5 JAM2 ENPEP CLDN7 EPHA1 TIMP3 EPHA3 VCAM1 EPHA5 CLDN5 EPHA7 MSN EPHB1 NOX3 EPHB2 ACTC1 EPHB4 VAV2 FGFR2 CLDN10 FZD1 RAP1GAP FZD10 VAV3 FZD5 MAPK10 FZD6 CTNNA2 GAB1 CDH5 GLI1 PECAM1 GLI3 CTNND1 GNA14 ITGA4 GNAI1 CLDN16 GNAO1 CLDN9 GNAS CLDN15 GNB4 CLDN22 GNG11 OCLN GNG2 ESAM Gallego-Martinez A, et al. J Med Genet 2019; 0:1–7. doi: 10.1136/jmedgenet-2019-106159 Supplementary material J Med Genet GNG7 ACTB IGF1 CYBA IRS1 CTNNB1 IRS2 MMP9 ITGA3 MAPK14 ITGB1 MAPK11 LIMK1 MAPK12 LIMK2 MAPK13 LINGO1 PRKCB LRRC4C PXN MME BCAR1 MMP11 THY1 MMP2 ARHGAP5 MRAS MYL2 MYL9 MYLPF NFATC4 RAP1A NGFR RAP1B NOTUM VASP NRP1 ACTN4 NTN3 ACTN1 NTRK2 VCL NTRK3 RAPGEF4 PAK3 ITK PAK4 VAV1 PAPPA2 PDGFA PDGFC PIK3CB PIK3R1 PLCE1 PLCH1 PLCH2 PLXNA2 PLXNB1 PLXND1 PPP3CA PRKACB PRKAR2A PRKAR2B PRKCA PRKCZ PRKD3 ROBO2 SDC2 SDCBP Gallego-Martinez A, et al. J Med Genet 2019; 0:1–7. doi: 10.1136/jmedgenet-2019-106159 Supplementary material J Med Genet SEMA3B SEMA3C SEMA3E SEMA3F SEMA4F SEMA4G SEMA5A SEMA6B SEMA6D SEMA7A SHC1 SLIT2 SLIT3 STK36 TUBA4A TUBB2B TUBB4A TUBB4B TUBB6 UNC5C UNC5D ENSG00000165197 WIPF1 WNT3 WNT5A WNT7A WNT7B NTNG1 NTNG2 LRRC4 NTN4 TRPC1 TRPC3 TRPC6 PPP3CB PPP3CC PPP3R1 NFATC2 NFATC3 PTK2 FYN RAC1 CDC42 ABLIM2 NCK1 PAK1 PAK2 Gallego-Martinez A, et al.
    [Show full text]
  • Defective Expression of Polarity Protein PAR-3 Gene (PARD3) in Esophageal Squamous Cell Carcinoma
    Oncogene (2009) 28, 2910–2918 & 2009 Macmillan Publishers Limited All rights reserved 0950-9232/09 $32.00 www.nature.com/onc ORIGINAL ARTICLE Defective expression of polarity protein PAR-3 gene (PARD3) in esophageal squamous cell carcinoma K Zen1, K Yasui1, Y Gen1, O Dohi1, N Wakabayashi1, S Mitsufuji1, Y Itoh1, Y Zen2, Y Nakanuma2, M Taniwaki3, T Okanoue1,4 and T Yoshikawa1 1Department of Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan; 2Department of Human Pathology, Kanazawa University Graduate School of Medicine, Kanazawa, Japan; 3Department of Molecular Hematology and Oncology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan and 4Department of Hepatology, Saiseikai Suita Hospital, Suita, Japan The partition-defective 3 (PAR-3) protein is implicated in Inactivation of tumor suppressor genes is critical to the formation of tight junctions at epithelial cell–cell the development and progression of human malignan- contacts. We investigated DNA copy number aberrations cies. Much effort has been put into finding homozygous in human esophageal squamous cell carcinoma (ESCC) deletions in cancer cells in the expectation that they cell lines using a high-density oligonucleotide microarray harbor tumor suppressor genes. Suppressor genes that and found a homozygous deletion of PARD3 (the gene have been identified partly from homozygous deletions encoding PAR-3). Exogenous expression of PARD3 in include CDKN2A (Kamb et al., 1994), PTEN (Li et al., ESCC cells lacking this gene enhanced the recruitment 1997) and SMAD4 (Hahn et al., 1996). The recent of zonula occludens 1 (ZO-1), a marker of tight junctions, introduction of high-density oligonucleotide micro- to sites of cell–cell contact.
    [Show full text]
  • Using Mechanistic Models for the Clinical Interpretation of Complex Genomic Variation María Peña-Chilet1,2, Marina Esteban-Medina1, Matias M
    www.nature.com/scientificreports OPEN Using mechanistic models for the clinical interpretation of complex genomic variation María Peña-Chilet1,2, Marina Esteban-Medina1, Matias M. Falco1,2, Kinza Rian1, Marta R. Hidalgo3, Carlos Loucera 1 & Joaquín Dopazo 1,2,4* The sustained generation of genomic data in the last decade has increased the knowledge on the causal mutations of a large number of diseases, especially for highly penetrant Mendelian diseases, typically caused by a unique or a few genes. However, the discovery of causal genes in complex diseases has been far less successful. Many complex diseases are actually a consequence of the failure of complex biological modules, composed by interrelated proteins, which can happen in many diferent ways, which conferring a multigenic nature to the condition that can hardly be attributed to one or a few genes. We present a mechanistic model, Hipathia, implemented in a web server that allows estimating the efect that mutations, or changes in the expression of genes, have over the whole system of human signaling and the corresponding functional consequences. We show several use cases where we demonstrate how diferent the ultimate impact of mutations with similar loss-of-function potential can be and how the potential pathological role of a damaged gene can be inferred within the context of a signaling network. The use of systems biology-based approaches, such as mechanistic models, allows estimating the potential impact of loss-of-function mutations occurring in proteins that are part of complex biological interaction networks, such as signaling pathways. This holistic approach provides an elegant alternative to gene-centric approaches that can open new avenues in the interpretation of the genomic variability in complex diseases.
    [Show full text]
  • PDF Output of CLIC (Clustering by Inferred Co-Expression)
    PDF Output of CLIC (clustering by inferred co-expression) Dataset: Num of genes in input gene set: 88 Total number of genes: 16493 CLIC PDF output has three sections: 1) Overview of Co-Expression Modules (CEMs) Heatmap shows pairwise correlations between all genes in the input query gene set. Red lines shows the partition of input genes into CEMs, ordered by CEM strength. Each row shows one gene, and the brightness of squares indicates its correlations with other genes. Gene symbols are shown at left side and on the top of the heatmap. 2) Details of each CEM and its expansion CEM+ Top panel shows the posterior selection probability (dataset weights) for top GEO series datasets. Bottom panel shows the CEM genes (blue rows) as well as expanded CEM+ genes (green rows). Each column is one GEO series dataset, sorted by their posterior probability of being selected. The brightness of squares indicates the gene's correlations with CEM genes in the corresponding dataset. CEM+ includes genes that co-express with CEM genes in high-weight datasets, measured by LLR score. 3) Details of each GEO series dataset and its expression profile: Top panel shows the detailed information (e.g. title, summary) for the GEO series dataset. Bottom panel shows the background distribution and the expression profile for CEM genes in this dataset. Overview of Co-Expression Modules (CEMs) with Dataset Weighting Scale of average Pearson correlations Num of Genes in Query Geneset: 88. Num of CEMs: 1. 0.0 0.2 0.4 0.6 0.8 1.0 Cldn7 Epcam Marveld2 Cldn3 Cldn4 Pard6b Ocln
    [Show full text]