DOCSLIB.ORG

Crmps: Critical Molecules for Neurite Morphogenesis and Neuropsychiatric Diseases

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Crmps: Critical Molecules for Neurite Morphogenesis and Neuropsychiatric Diseases Molecular Psychiatry (2015) 20, 1037–1045 © 2015 Macmillan Publishers Limited All rights reserved 1359-4184/15 www.nature.com/mp REVIEW CRMPs: critical molecules for neurite morphogenesis and neuropsychiatric diseases TT Quach1,2, J Honnorat1,3,4, PE Kolattukudy5, R Khanna6 and AM Duchemin7 Neuronal polarity and spatial rearrangement of neuronal processes are central to the development of all mature nervous systems. Recent studies have highlighted the dynamic expression of Collapsin-Response-Mediator Proteins (CRMPs) in neuronal dendritic/ axonal compartments, described their interaction with cytoskeleton proteins, identified their ability to activate L- and N-type voltage-gated calcium channels (VGCCs) and delineated their crucial role as signaling molecules essential for neuron differentiation and neural network development and maintenance. In addition, evidence obtained from genome-wide/genetic linkage/proteomic/ translational approaches revealed that CRMP expression is altered in human pathologies including mental (schizophrenia and mood disorders) and neurological (Alzheimer’s, prion encephalopathy, epilepsy and others) disorders. Changes in CRMPs levels have been observed after psychotropic treatments, and disrupting CRMP2 binding to calcium channels blocked neuropathic pain. These observations, altogether with those obtained from genetically modified mice targeting individual CRMPs and RNA interference approaches, pave the way for considering CRMPs as potential early disease markers and modulation of their activity as therapeutic strategy for disorders associated with neurite abnormalities. Molecular Psychiatry (2015) 20, 1037–1045; doi:10.1038/mp.2015.77; published online 16 June 2015 The ability of the nervous system to process continuously maintenance of axodendritic arborization and discuss their changing information from the internal and external environ- potential involvement in human nervous system diseases. ments requires the development of precise networks of neurons and structural plasticity of their dendrites and axons. Considering the intricacies of specific axodendritic connectivity, it is surprising CRMPS: CHARACTERISTICS AND EXPRESSION that neurons can undergo such precise structural reorganization in CRMPs are five homologous cytosolic phosphoproteins.6–8 CRMP1, response to environmental change. However, evidence indicates 2, 3 and 4 display 75% homology with each other,9–11 whereas that far from being static structures, axons and dendrites are the phylogenetically divergent CRMP5/CRAM shares only 50% plastic and this plasticity, which is part of a lifelong process, is homology.12 CRMP1, 2 and 4 have two distinct alternatively mediated by various proteins such as neurotrophic/transcription spliced isoforms in their N termini,13 extending the number of factors, neurohormones, guidance cues, membrane receptors, active molecules in this family. All CRMPs assemble in heterophilic voltage-gated calcium channels (VGCCs) and involves rearrange- oligomers in vivo, bind to tubulin14 and are phosphorylated by ment of cytoskeletal proteins that support the structural changes.1 various kinases that regulate their activity.15 They act as signaling However, despite the rich information on mechanisms underlying phosphoproteins modulating cytoskeletal organization and neuronal differentiation, axonogenesis and dendritogenesis, the regulating neurite formation and retraction. Site-specific phos- key molecules involved in the initiation of neurites through phorylation of CRMPs determines their affinity for binding to cyto- formation of lamellopodia/filopodia, specification and maturation skeletal proteins and their neurite-promoting/collapsing activities. – of neurites, and genesis of spines still remain elusive.2 3 Because CRMP1 appears to be a target of RhoA signaling.16 The Sema3A17 such a large fraction of the genome is expressed in the brain and and reelin18 signaling pathways are regulated by the phosphor- our knowledge of mechanisms involved in neuronal connectivity ylation of CRMP1 by Cdk5 at Thr-509 and Ser-522, or by Fyn at is still in its infancy, it has been postulated that more mole- Tyr-504 that lowers its binding affinity to tubulin. Similarly, non- cular cues and pathways specialized for axonal/dendritic/spine phosphorylated CRMP2 binds strongly to tubulin leading to genesis and synaptic network formation remain to be iden- microtubule formation, whereas its phosphorylation by Rho kinase tified. Consistent with this notion, Collapsin-Response-Mediator suppresses its binding to tubulin and Numb.14 Two other kinases Proteins (CRMPs) can now be considered as building blocks for working in tandem, Cdk5 and GSK-3β, also control the interaction neuronal differentiation and neurite network organization and of CRMP2 with tubulin. In addition, CRMP2 regulates the stability remodeling.4–5 In this review, we outline the current evidence of actin filaments.19 CRMP3 is phosphorylated by Fyn in vitro15 but showing that CRMPs are important in the establishment and is unique among CRMPs in that the three GSK-3β phosphorylation 1Lyon Neuroscience Research Center, INSERM U1028/CNRS UMR 5292, F-69372 Lyon, France; 2Department of Neuroscience, The Ohio State University, Columbus, OH, USA; 3French Reference Center on Paraneoplastic Neurological Syndrome, Hospices Civils de Lyon, Hôpital Neurologique, Neurologie B, Bron, France; 4Université de Lyon, Université Claude Bernard Lyon 1, F-69372 Lyon, France; 5Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, Orlando, FL, USA; 6Department of Pharmacology and Neuroscience, Graduate Interdisciplinary Program, College of Medicine, The University of Arizona, Tucson, AZ, USA and 7Department of Psychiatry, College of Medicine, The Ohio State University, Columbus, OH, USA. Correspondence: Dr AM Duchemin, Department of Psychiatry, College of Medicine, The Ohio State University, Columbus, OH 43210, USA. E-mail: [email protected] Received 7 November 2014; revised 29 April 2015; accepted 8 May 2015; published online 16 June 2015 CRMPs in neuron development and diseases TT Quach et al 1038 Table 1. Summary of relative CRMP expression pattern in mouse nervous system Cortex Hippocampus Dentate gyrus Striatum Cerebellum Pons DRG CRMP1 ePN + + + ? +++ ? ? Adult ++ +++ ++ ? +++ ? ? CRMP2 ePN ++ ++ ++ ++ ++ ? ++ Adult ++ +++ ++ + ++ ? + CRMP3 ePN − +++ +++ − +++1 ++ Adult − +++ +++ −−++1 − CRMP4 ePN ++ +++ +++ + + +2 ? Adult − ++−−−+ CRMP5 ePN + + + ? + ? ? Adult + ++ ++ + ++ ? ? Abbreviations: DRG, dorsal root ganglia; ePN, early postnatal. (1), inferior olive complex and reticular formation; (2), pontine nuclei. Data from refs 9,12,13,23,29,31,32,44,46,48,127–129; +++, high level; ++, moderate level; +, low level; − , undetectable signal; ?, not determined. sites identified in other CRMPs are not conserved in this molecule. activation of L- and N-type VGCCs by CRMP3 provide strong CRMP4, which binds to F-actin and regulates F-actin bundling,20 is support for an inductive role of CRMP3 in neurite initiation and also a physiological partner of GSK-3β.21 Of note, GSK-3β is a dendritic development and plasticity, at least partly via Ca2+ ubiquitous protein kinase having a pivotal role in neurodevelop- influx29 (Figure 1d). In contrast, CRMP5 depletion by RNA ment and is suspected to be involved in neuropsychiatric interference enhances the length and number of neurites, disorders such as schizophrenia,22 bipolar disorders23 and whereas its overexpression induces mitophagy and reduces Alzheimer’s disease (AD).24 CRMP5 is a substrate for Cdk525 and dendritic length. Further, overexpression of mutated-Threo-516 26 is tyrosine-phosphorylated by Fes/Fps and TrkB. In view of these CRMP5 (ref. 34) and/or its truncated dominant-negative isoform observations, we can conclude that, depending on the character- lacking the tubulin-binding domain35 has no effect on dendrite istics of their phosphorylation status, CRMPs may associate with formation or length, demonstrating the critical role of the tubulin- 27 various partners and signaling pathways, some of which may binding domain in the neurite outgrowth inhibition induced by exclude direct interaction between them in different brain areas. CRMP5. The interaction of CRMP5 with tubulin has important 28 29 30 In addition, CRMP2, CRMP3 and CRMP4 have been shown to ramifications for the function of CRMP2. Consistent with the modulate calcium flux, another mechanism of neurite regulation. 10 31 notion that the activities of CRMPs are inter-related, dendritic According to in situ hybridization, immunostaining and arborization induced by CRMP2 is considerably enhanced by 32 fi gene replacement analyses, all ve CRMPs are highly expressed CRMP5 deficiency.36 There is also evidence that CRMP4 regulates in the brain during early postnatal development and continue to dendritic outgrowth: CRMP4–short hairpin RNA-transfected be present in specific regions into adulthood, especially in areas and CRMP4 − / − cultured hippocampal neurons show increased with extensive neuronal plasticity (Table 1). They are found in dendritic branching without significant changes in primary axons and dendrites of the neurons where they contribute to dendrite number.37 This effect is partly dependent on Sema3A specific signaling mechanisms involved in the regulation of axonal signaling through F-actin bundling.20 Phosphorylated CRMP1 and and dendritic development and maintenance. CRMP2 are localized in the dendrites of cortical neurons where they regulate dendritic branch
Load more

Recommended publications
  • Deregulated Gene Expression Pathways in Myelodysplastic Syndrome Hematopoietic Stem Cells
    Leukemia (2010) 24, 756–764 & 2010 Macmillan Publishers Limited All rights reserved 0887-6924/10 $32.00 www.nature.com/leu ORIGINAL ARTICLE Deregulated gene expression pathways in myelodysplastic syndrome hematopoietic stem cells A Pellagatti1, M Cazzola2, A Giagounidis3, J Perry1, L Malcovati2, MG Della Porta2,MJa¨dersten4, S Killick5, A Verma6, CJ Norbury7, E Hellstro¨m-Lindberg4, JS Wainscoat1 and J Boultwood1 1LRF Molecular Haematology Unit, NDCLS, John Radcliffe Hospital, Oxford, UK; 2Department of Hematology Oncology, University of Pavia Medical School, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy; 3Medizinische Klinik II, St Johannes Hospital, Duisburg, Germany; 4Division of Hematology, Department of Medicine, Karolinska Institutet, Stockholm, Sweden; 5Department of Haematology, Royal Bournemouth Hospital, Bournemouth, UK; 6Albert Einstein College of Medicine, Bronx, NY, USA and 7Sir William Dunn School of Pathology, University of Oxford, Oxford, UK To gain insight into the molecular pathogenesis of the the World Health Organization.6,7 Patients with refractory myelodysplastic syndromes (MDS), we performed global gene anemia (RA) with or without ringed sideroblasts, according to expression profiling and pathway analysis on the hemato- poietic stem cells (HSC) of 183 MDS patients as compared with the the French–American–British classification, were subdivided HSC of 17 healthy controls. The most significantly deregulated based on the presence or absence of multilineage dysplasia. In pathways in MDS include interferon signaling, thrombopoietin addition, patients with RA with excess blasts (RAEB) were signaling and the Wnt pathways. Among the most signifi- subdivided into two categories, RAEB1 and RAEB2, based on the cantly deregulated gene pathways in early MDS are immuno- percentage of bone marrow blasts.
    [Show full text]
  • Integrative Analysis Identifies Candidate Tumor Microenvironment and Intracellular Signaling Pathways That Define Tumor Heterogeneity in NF1
    bioRxiv preprint doi: https://doi.org/10.1101/2020.01.13.904771; this version posted January 15, 2020. 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. Integrative analysis identifies candidate tumor microenvironment and intracellular signaling pathways that define tumor heterogeneity in NF1 Jineta Banerjee1#, Robert J Allaway1#, Jaclyn N Taroni2, Aaron Baker1,4, Xiaochun Zhang5, Chang In Moon5, Jaishri O Blakeley6, Justin Guinney1, Angela Hirbe5, Casey S Greene2,3, Sara JC Gosline1* 1 Computational Oncology, Sage Bionetworks, Seattle, WA, 98121 2 Childhood Cancer Data LaB, Alex's Lemonade Stand Foundation, Philadelphia, PA, 19102 3 Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104 4 University of Wisconsin-Madison, Madison, WI, 53715 5 Division of Oncology, Washington University Medical School, St. Louis, MO 63110 6 Neurology, Neurosurgery and Oncology, Johns Hopkins University, Baltimore, MD 21287 # Equal ContriBution * Correspondence: [email protected] Abstract: NeurofiBromatosis type 1 is a monogenic syndrome that gives rise to numerous symptoms including cognitive impairment, skeletal aBnormalities, and growth of Benign nerve sheath tumors. Nearly all NF1 patients develop cutaneous neurofiBromas (cNFs), which occur on the skin surface, while 40-60% of patients develop plexiform neurofibromas (pNFs) which are deeply embedded in the peripheral nerves. Patients with pNFs have a ~10% lifetime chance of these tumors Becoming malignant peripheral nerve sheath tumors (MPNSTs). These tumors have a severe prognosis and few treatment options other than surgery.
    [Show full text]
  • Genome-Wide Analysis of Thyroid Hormone Receptors Shared and Specific Functions in Neural Cells
    Genome-wide analysis of thyroid hormone receptors shared and specific functions in neural cells Fabrice Chatonneta, Romain Guyota, Gérard Benoîtb, and Frederic Flamanta,1 aInstitut de Génomique Fonctionnelle de Lyon, Université de Lyon, Centre National de la Recherche Scientifique (CNRS), Institut National de la Recherche Agronomique, École Normale Supérieure de Lyon, 69364 Lyon Cedex 07, France; and bCentre de Génétique et de Physiologie Moléculaire et Cellulaire, CNRS, Université Lyon 1, Unité Mixte de Recherche 5334, Villeurbanne F-69622, France Edited by Pierre Chambon, Institut de Génétique et de Biologie Moléculaire et Cellulaire (Centre National de la Recherche Scientifique UMR7104, Institut National de la Santé et de la Recherche Médicale U596, Université de Strasbourg, College de France), Illkirch-Cedex, France, and approved January 4, 2013 (received for review June 25, 2012) TRα1 and TRβ1, the two main thyroid hormone receptors in mam- issue. It would help to develop new selective ligands (6). It might mals, are transcription factors that share similar properties. How- also help to predict the possible detrimental side effects of these ever, their respective functions are very different. This functional synthetic ligands in heart and brain (7) and the toxicity of some divergence might be explained in two ways: it can reflect different environmental contaminants supposed to interfere with TR expression patterns or result from different intrinsic properties of functions (8). The primary sequence and 3D structure of TRα1 β the receptors. We tested this second hypothesis by comparing the and TR 1 are very similar, although differences are observed for – repertoires of 3,3′,5-triiodo-L-thyronine (T3)-responsive genes of key amino acids in the DNA-binding domain (9 12).
    [Show full text]
  • Identification of Transcriptional Mechanisms Downstream of Nf1 Gene Defeciency in Malignant Peripheral Nerve Sheath Tumors Daochun Sun Wayne State University
    Wayne State University DigitalCommons@WayneState Wayne State University Dissertations 1-1-2012 Identification of transcriptional mechanisms downstream of nf1 gene defeciency in malignant peripheral nerve sheath tumors Daochun Sun Wayne State University, Follow this and additional works at: http://digitalcommons.wayne.edu/oa_dissertations Recommended Citation Sun, Daochun, "Identification of transcriptional mechanisms downstream of nf1 gene defeciency in malignant peripheral nerve sheath tumors" (2012). Wayne State University Dissertations. Paper 558. This Open Access Dissertation is brought to you for free and open access by DigitalCommons@WayneState. It has been accepted for inclusion in Wayne State University Dissertations by an authorized administrator of DigitalCommons@WayneState. IDENTIFICATION OF TRANSCRIPTIONAL MECHANISMS DOWNSTREAM OF NF1 GENE DEFECIENCY IN MALIGNANT PERIPHERAL NERVE SHEATH TUMORS by DAOCHUN SUN DISSERTATION Submitted to the Graduate School of Wayne State University, Detroit, Michigan in partial fulfillment of the requirements for the degree of DOCTOR OF PHILOSOPHY 2012 MAJOR: MOLECULAR BIOLOGY AND GENETICS Approved by: _______________________________________ Advisor Date _______________________________________ _______________________________________ _______________________________________ © COPYRIGHT BY DAOCHUN SUN 2012 All Rights Reserved DEDICATION This work is dedicated to my parents and my wife Ze Zheng for their continuous support and understanding during the years of my education. I could not achieve my goal without them. ii ACKNOWLEDGMENTS I would like to express tremendous appreciation to my mentor, Dr. Michael Tainsky. His guidance and encouragement throughout this project made this dissertation come true. I would also like to thank my committee members, Dr. Raymond Mattingly and Dr. John Reiners Jr. for their sustained attention to this project during the monthly NF1 group meetings and committee meetings, Dr.
    [Show full text]
  • Downloaded from Bioscientifica.Com at 10/06/2021 09:24:43AM Via Free Access
    249 A Di Domenico et al. Genetics and epigenetics 24:9 R315–R334 Review of NET Genetic and epigenetic drivers of neuroendocrine tumours (NET) Correspondence Annunziata Di Domenico1,2, Tabea Wiedmer1,2, Ilaria Marinoni1,* and Aurel Perren1,* should be addressed to I Marinoni or A Perren 1 Institute of Pathology, University of Bern, Bern, Switzerland Email 2 Graduate School for Cellular and Biomedical Sciences, University of Bern, Bern, Switzerland ilaria.marinoni@pathology. *(I Marinoni and A Perren contributed equally to this work) unibe.ch or aurel.perren@ pathology.unibe.ch Abstract Neuroendocrine tumours (NET) of the gastrointestinal tract and the lung are a rare Key Words and heterogeneous group of tumours. The molecular characterization and the clinical f genetic classification of these tumours have been evolving slowly and show differences according f genomic to organs of origin. Novel technologies such as next-generation sequencing revealed new f epigenetic molecular aspects of NET over the last years. Notably, whole-exome/genome sequencing f pancreatic NET (WES/WGS) approaches underlined the very low mutation rate of well-differentiated f lung NET and small NET of all organs compared to other malignancies, while the engagement of epigenetic intestinal NET changes in driving NET evolution is emerging. Indeed, mutations in genes encoding f DNA methylation for proteins directly involved in chromatin remodelling, such as DAXX and ATRX are f chromatin a frequent event in NET. Epigenetic changes are reversible and targetable; therefore, f histone modification an attractive target for treatment. The discovery of the mechanisms underlying the epigenetic changes and the implication on gene and miRNA expression in the different Endocrine-Related Cancer Endocrine-Related subgroups of NET may represent a crucial change in the diagnosis of this disease, reveal new therapy targets and identify predictive markers.
    [Show full text]
  • Full Text (PDF)
    Published OnlineFirst November 10, 2009; DOI: 10.1158/0008-5472.CAN-09-1778 Cell, Tumor, and Stem Cell Biology Loss of Collapsin Response Mediator Protein1, as Detected by iTRAQ Analysis, Promotes Invasion of Human Gliomas Expressing Mutant EGFRvIII Joydeep Mukherjee,1 Leroi V. DeSouza,2 Johann Micallef,1 Zia Karim,1 Sid Croul,3 K.W. Michael Siu,2 and Abhijit Guha1,4 1Arthur and Sonia Labatts Brain Tumor Research Center, Hospital for Sick Children's Research Institute, University of Toronto, 2Department of Chemistry and Centre for Research in Mass Spectrometry, York University, 3Division of Neuropathology, Department of Pathology, Toronto Western Hospital, University of Toronto, and 4Division of Neurosurgery, Department of Surgery, Toronto Western Hospital, University of Toronto, Toronto, Canada Abstract cellular domain of the 180-kDa wtEGFR. This mutant EGFR, Δ – Glioblastoma multiforme (GBM) is the most common and le- termed EGFR, de2-7 EGFR, or most commonly EGFRvIII (4 7), ∼ thal primary human brain tumor. GBMs are characterized by results in a truncated 140-kDa constitutively activated EGFRvIII, a variety of genetic alterations, among which oncogenic muta- with an identical intracellular domain to wtEGFR (3, 4, 8). Preclin- tions of epidermal growth factor receptor (EGFRvIII) is most ical studies have shown that GBMs that harbor EGFRvIII have an in vitro in vivo common. GBMs harboring EGFRvIII have increased prolifera- and growth advantage, compared with GBMs that tion and invasive characteristics versus those expressing wild- just overexpress wtEGFR (9). Clinical studies suggest that the ∼ type (wt) EGFR. To identify the molecular basis of this 25% of all GBM patients whose tumors express both EGFRvIII increased tumorgenic phenotype, we used iTRAQ-labeling dif- and wtEGFR have a shorter interval to relapse and decreased sur- ferential proteomic analysis.
    [Show full text]
  • Clinical Evidence That a Dysregulated Master Neural Network Modulator May Aid in Diagnosing Schizophrenia
    Clinical evidence that a dysregulated master neural network modulator may aid in diagnosing schizophrenia Munetaka Nomotoa,b,1, Glenn T. Konopaskec,d,1, Naoya Yamashitab, Reina Aokib, Aoi Jitsuki-Takahashib, Haruko Nakamurab,e, Hiroko Makiharab,f, Mari Saitog, Yusuke Saigusag, Fumio Nakamurab, Keisuke Watanabeh, Toshihiko Babah, Francine M. Benesc, Brian T. D. Tobei, Cameron D. Perniac,i, Joseph T. Coylec, Richard L. Sidmanj,2, Yoshio Hirayasua, Evan Y. Snyderi,2, and Yoshio Goshimab,2 aDepartment of Psychiatry, Yokohama City University Graduate School of Medicine, 236-0004 Yokohama, Japan; bDepartment of Molecular Pharmacology and Neurobiology, Yokohama City University Graduate School of Medicine, 236-0004 Yokohama, Japan; cDepartment of Psychiatry, Mailman Research Center, McLean Hospital, Harvard Medical School, Belmont, MA 02478; dDepartment of Psychiatry, University of Connecticut School of Medicine, Farmington, CT 06030; eDepartment of Neurology & Stroke Medicine, Yokohama City University Graduate School of Medicine, 236-0004 Yokohama, Japan; fBiological Science & Nursing, Yokohama City University Graduate School of Medicine, 236-0004 Yokohama, Japan; gDepartment of Biostatistics, Yokohama City University Graduate School of Medicine, 236-0004 Yokohama, Japan; hDepartment of Electrical & Computer Engineering, Graduate School of Engineering, Yokohama National University, 240-8501 Yokohama, Japan; iCenter for Stem Cells & Regenerative Medicine, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037; and jDepartment of Neurology, Harvard Medical School, Boston, MA 02115 Contributed by Richard L. Sidman, June 20, 2021 (sent for review January 2, 2021; reviewed by Cesario Borlongan and Rohn Friedman) There are no validated biomarkers for schizophrenia (SCZ), a facilitate that systematic examination of genes across larger more disorder linked to neural network dysfunction.
    [Show full text]
  • Effect of Prematurity on Genome Wide Methylation in the Placenta Jessica Schuster1, Alper Uzun2, Joan Stablia1, Christoph Schorl3, Mari Mori4 and James F
    Schuster et al. BMC Medical Genetics (2019) 20:116 https://doi.org/10.1186/s12881-019-0835-6 RESEARCH ARTICLE Open Access Effect of prematurity on genome wide methylation in the placenta Jessica Schuster1, Alper Uzun2, Joan Stablia1, Christoph Schorl3, Mari Mori4 and James F. Padbury2,5* Abstract Background: Preterm birth is a significant clinical problem and an enormous burden on society, affecting one in eight pregnant women and their newborns. Despite decades of research, the molecular mechanism underlying its pathogenesis remains unclear. Many studies have shown that preterm birth is associated with health risks across the later life course. The “fetal origins” hypothesis postulates that adverse intrauterine exposures are associated with later disease susceptibility. Our recent studies have focused on the placental epigenome at term. We extended these studies to genome-wide placental DNA methylation across a wide range of gestational ages. We applied methylation dependent immunoprecipitation/DNA sequencing (MeDIP-seq) to 9 placentas with gestational age from 25 weeks to term to identify differentially methylated regions (DMRs). Results: Enrichment analysis revealed 427 DMRs with nominally significant differences in methylation between preterm and term placentas (p < 0.01) and 21 statistically significant DMRs after multiple comparison correction (FDR p < 0.05), of which 62% were hypo-methylated in preterm placentas vs term placentas. The majority of DMRs were in distal intergenic regions and introns. Significantly enriched pathways identified by Ingenuity Pathway Analysis (IPA) included Citrulline-Nitric Oxide Cycle and Fcy Receptor Mediated Phagocytosis in macrophages. The DMR gene set overlapped placental gene expression data, genes and pathways associated evolutionarily with preterm birth.
    [Show full text]
  • Robles JTO Supplemental Digital Content 1
    Supplementary Materials An Integrated Prognostic Classifier for Stage I Lung Adenocarcinoma based on mRNA, microRNA and DNA Methylation Biomarkers Ana I. Robles1, Eri Arai2, Ewy A. Mathé1, Hirokazu Okayama1, Aaron Schetter1, Derek Brown1, David Petersen3, Elise D. Bowman1, Rintaro Noro1, Judith A. Welsh1, Daniel C. Edelman3, Holly S. Stevenson3, Yonghong Wang3, Naoto Tsuchiya4, Takashi Kohno4, Vidar Skaug5, Steen Mollerup5, Aage Haugen5, Paul S. Meltzer3, Jun Yokota6, Yae Kanai2 and Curtis C. Harris1 Affiliations: 1Laboratory of Human Carcinogenesis, NCI-CCR, National Institutes of Health, Bethesda, MD 20892, USA. 2Division of Molecular Pathology, National Cancer Center Research Institute, Tokyo 104-0045, Japan. 3Genetics Branch, NCI-CCR, National Institutes of Health, Bethesda, MD 20892, USA. 4Division of Genome Biology, National Cancer Center Research Institute, Tokyo 104-0045, Japan. 5Department of Chemical and Biological Working Environment, National Institute of Occupational Health, NO-0033 Oslo, Norway. 6Genomics and Epigenomics of Cancer Prediction Program, Institute of Predictive and Personalized Medicine of Cancer (IMPPC), 08916 Badalona (Barcelona), Spain. List of Supplementary Materials Supplementary Materials and Methods Fig. S1. Hierarchical clustering of based on CpG sites differentially-methylated in Stage I ADC compared to non-tumor adjacent tissues. Fig. S2. Confirmatory pyrosequencing analysis of DNA methylation at the HOXA9 locus in Stage I ADC from a subset of the NCI microarray cohort. 1 Fig. S3. Methylation Beta-values for HOXA9 probe cg26521404 in Stage I ADC samples from Japan. Fig. S4. Kaplan-Meier analysis of HOXA9 promoter methylation in a published cohort of Stage I lung ADC (J Clin Oncol 2013;31(32):4140-7). Fig. S5. Kaplan-Meier analysis of a combined prognostic biomarker in Stage I lung ADC.
    [Show full text]
  • Differentially Expressed Proteins in Glioblastoma Multiforme Identified
    www.impactjournals.com/oncotarget/ Oncotarget, 2017, Vol. 8, (No. 27), pp: 44141-44158 Research Paper Differentially expressed proteins in glioblastoma multiforme identified with a nanobody-based anti-proteome approach and confirmed by OncoFinder as possible tumor-class predictive biomarker candidates Ivana Jovčevska1, Neja Zupanec1, Žiga Urlep2, Andrej Vranič3, Boštjan Matos4, Clara Limbaeck Stokin5, Serge Muyldermans6, Michael P. Myers7, Anton A. Buzdin8,9, Ivan Petrov10,11 and Radovan Komel1 1Medical Center for Molecular Biology, Institute of Biochemistry, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia 2Center for Functional Genomics and Bio-Chips, Institute of Biochemistry, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia 3Department of Neurosurgery, Foundation Rothschild, Paris, France 4Department of Neurosurgery, University Clinical Center, Ljubljana, Slovenia 5Institute of Histopathology, Charing Cross Hospital, London, United Kingdom 6Cellular and Molecular Immunology, Vrije Universiteit Brussel, Brussels, Belgium 7International Center for Genetic Engineering and Biotechnology, Trieste, Italy 8First Oncology Research and Advisory Center, Moscow, Russia 9National Research Center 'Kurchatov Institute', Center of Convergence of Nano-, Bio-, Information and Cognitive Sciences and Technologies, Moscow, Russia 10Center for Biogerontology and Regenerative Medicine, IC Skolkovo, Moscow, Russia 11Moscow Institute of Physics and Technology, Moscow, Russia Correspondence to: Radovan Komel, email: [email protected] Ivana Jovčevska, email: [email protected] Keywords: glioblastoma multiforme, biomarkers, nanobodies, cancer biology, OncoFinder Received: September 14, 2016 Accepted: April 10, 2017 Published: April 24, 2017 Copyright: Jovčevska et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License 3.0 (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
    [Show full text]
  • A Radiation Hybrid Map of Chicken Chromosome 4
    A radiation hybrid map of chicken Chromosome 4 Tarik S.K.M. Rabie,1* Richard P.M.A. Crooijmans,1 Mireille Morisson,2 Joanna Andryszkiewicz,1 Jan J. van der Poel,1 Alain Vignal,2 Martien A.M. Groenen1 1Wageningen Institute of Animal Sciences, Animal Breeding and Genetics Group, Wageningen University, Marijkeweg 40, 6709 PG Wageningen, The Netherlands 2Laboratoire de ge´ne´tique cellulaire, Institut national de la recherche agronomique, 31326 Castanet-Tolosan, France Received: 15 December 2003 / Accepted: 16 March 2004 Comparative genomics plays an important role in Abstract the understanding of genome dynamics during ev- The mapping resolution of the physical map for olution and as a tool for the transfer of mapping chicken Chromosome 4 (GGA4) was improved by a information from species with gene-dense maps to combination of radiation hybrid (RH) mapping and species whose maps are less well developed (O‘Bri- bacterial artificial chromosome (BAC) mapping. The en et al. 1993, 1999). For farm animals, therefore, ChickRH6 hybrid panel was used to construct an RH the human and mouse have been the logical choice map of GGA4. Eleven microsatellites known to be as the model species used for this comparison. located on GGA4 were included as anchors to the Medium-resolution comparative maps have been genetic linkage map for this chromosome. Based on published for many of the livestock species, in- the known conserved synteny between GGA4 and cluding pig, cattle, sheep, and horse, identifying human Chromosomes 4 and X, sequences were large regions of conserved synteny between these identified for the orthologous chicken genes from species and man and mouse.
    [Show full text]
  • Underexpression of HOXA11 Is Associated with Treatment Resistance and Poor Prognosis in Glioblastoma
    pISSN 1598-2998, eISSN 2005-9256 Cancer Res Treat. 2017;49(2):387-398 https://doi.org/10.4143/crt.2016.106 Original Article Open Access Underexpression of HOXA11 Is Associated with Treatment Resistance and Poor Prognosis in Glioblastoma Young-Bem Se, MD1 Purpose Seung Hyun Kim, MD2 Homeobox (HOX) genes are essential developmental regulators that should normally be in the silenced state in an adult brain. The aberrant expression of HOX genes has been asso- Ji Young Kim, MS1 ciated with the prognosis of many cancer types, including glioblastoma (GBM). This study PhD1 Ja Eun Kim, examined the identity and role of HOX genes affecting GBM prognosis and treatment 1 Yun-Sik Dho, MD resistance. Jin Wook Kim, MD, PhD1 Yong Hwy Kim, MD1 Materials and Methods The full series of HOX genes of five pairs of initial and recurrent human GBM samples were Hyun Goo Woo, MD, PhD3 screened by microarray analysis to determine the most plausible candidate responsible for MD, PhD4 Se-Hyuk Kim, GBM prognosis. Another 20 newly diagnosed GBM samples were used for prognostic vali- 5 Shin-Hyuk Kang, MD, PhD dation. In vitro experiments were performed to confirm the role of HOX in treatment resist- 6 Hak Jae Kim, MD, PhD ance. Mediators involved in HOX gene regulation were searched using differentially Tae Min Kim, MD, PhD7 expressed gene analysis, gene set enrichment tests, and network analysis. Soon-Tae Lee, MD, PhD8 Results MD, PhD9 Seung Hong Choi, The underexpression of HOXA11 was identified as a consistent signature for a poor prog- 10 Sung-Hye Park, MD, PhD nosis among the HOX genes.
    [Show full text]