Differential Gene Expression in the Peripheral Zone Compared to the Transition Zone of the Human Prostate Gland
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UNIVERSITY of CALIFORNIA, IRVINE Netrin-Mediated Signaling
UNIVERSITY OF CALIFORNIA, IRVINE Netrin-mediated signaling directs central neuron dendrite growth and connectivity in the developing vertebrate visual system DISSERTATION submitted in partial satisfaction of the requirements for the degree of DOCTOR OF PHILOSOPHY in Biological Sciences by Anastasia Nicole Nagel Dissertation Committee: Professor Susana Cohen-Cory, Chair Associate Professor Karina S. Cramer Professor Georg F. Striedter 2015 © 2015 Anastasia Nicole Nagel DEDICATION To those who have supported me in my pursuit of understanding the natural world: my husband, family, friends and those who we have lost along the way but who remain present in spirit. “There are naive questions, tedious questions, ill-phrased questions, questions put after inadequate self-criticism. But every question is a cry to understand the world. There is no such thing as a dumb question.” Carl Sagan, The Demon-Haunted World: Science as a Candle in the Dark ii TABLE OF CONTENTS Page LIST OF FIGURES iv ACKNOWLEDGMENTS vi CURRICULUM VITAE vii ABSTRACT OF THE DISSERTATION x INTRODUCTION 1 CHAPTER 1: Molecular signals regulate visual system development 4 Netrin regulates neurodevelopment through diverse receptor binding 9 The role of netrin-1 in retinotectal circuit formation 19 Summary and objectives 27 CHAPTER 2: Netrin directs dendrite growth and connectivity in vivo 29 Introduction 29 Materials and Methods 31 Results 36 Discussion 64 CHAPTER 3: DCC and UNC5 Netrin receptor signaling guides dendritogenesis 70 Introduction 70 Materials and Methods 72 Results 77 Discussion 102 CHAPTER 4: Decreases in Netrin signaling impact visual system function 113 Introduction 113 Materials and Methods 114 Results 116 Discussion 121 CHAPTER 5: Summary and Conclusions 122 REFERENCES 129 iii LIST OF FIGURES Page Figure 1.1 Neuron during general developmental processes 5 Figure 1.2 Signaling molecules that direct visual system formation 8 Figure 1.3 Schematic representation of a netrin-1 gradient in the spinal cord 13 Figure 1.4 Diagram of the X. -
Promotion of Neurite Outgrowth and Axon Guidance in Spiral Ganglion Cells by Netrin-1
ORIGINAL ARTICLE Promotion of Neurite Outgrowth and Axon Guidance in Spiral Ganglion Cells by Netrin-1 Kenneth H. Lee, MD, PhD; Mark E. Warchol, PhD Objective: To identify the expression of netrin-1, a Results: Netrin-1 and DCC mRNA expression were found diffusible chemoattractive molecule, and its receptor, in the mouse organ of Corti and spiral ganglion cells by deleted in colorectal carcinoma (DCC), in the devel- RT-PCR. Application of exogenous netrin-1 led to a dos- opmentally mature inner ear, and to determine its age-dependent increase in neurite length in cultured spi- effects on axon length and guidance in cultured auditory ral ganglion cells. Chick acoustic ganglion cells cocul- neurons. tured with netrin-1–secreting cells demonstrated statistically significant preferential extension toward the source of netrin-1 (P =.04). Design: Messenger RNA (mRNA) and protein expres- sion of netrin-1 and DCC were identified in the organ of Conclusions: Netrin-1 and DCC are expressed in the or- Corti and spiral ganglion cells using reverse transcription– gan of Corti and spiral ganglion cells of developmen- polymerase chain reaction (RT-PCR) and fluorescence tally mature mice. Exogenous netrin-1 promotes dosage- immunohistochemical analysis. In vitro experiments ex- dependent neurite growth in vitro. Mature auditory amined the effects of exogenous netrin-1 on spiral gan- neurons preferentially direct neurite extension toward glion cell axon length. Auditory neurons were cocul- netrin-1 released in culture. These findings may lead to tured with a cell line secreting netrin-1 to determine the the development of strategies to optimize the interface effect on direction of axon extension. -
Clinical Utility Gene Card For: 3-M Syndrome – Update 2013
European Journal of Human Genetics (2014) 22, doi:10.1038/ejhg.2013.156 & 2014 Macmillan Publishers Limited All rights reserved 1018-4813/14 www.nature.com/ejhg CLINICAL UTILITY GENE CARD UPDATE Clinical utility gene card for: 3-M syndrome – Update 2013 Muriel Holder-Espinasse*,1, Melita Irving1 and Vale´rie Cormier-Daire2 European Journal of Human Genetics (2014) 22, doi:10.1038/ejhg.2013.156; published online 31 July 2013 Update to: European Journal of Human Genetics (2011) 19, doi:10.1038/ejhg.2011.32; published online 2 March 2011 1. DISEASE CHARACTERISTICS nonsense and missense mutations c.4333C4T (p.Arg1445*) and 1.1 Name of the disease (synonyms) c.4391A4C (p.His1464Pro), respectively, render CUL7 deficient 3-M syndrome (gloomy face syndrome, dolichospondylic dysplasia). in recruiting ROC1, leading to impaired ubiquitination. OBSL1: microsatellites analysis of the locus (2q35-36.1) in con- 1.2 OMIM# of the disease sanguineous families. OBSL1: microsatellites analysis of the locus 273750. (2q35-36.1) in consanguineous families. Mutations induce non- sense mediated decay. Knockdown of OBSL1 in HEK293 cells 1.3 Name of the analysed genes or DNA/chromosome segments shows the role of this gene in the maintenance of normal levels of CUL7, OBSL1 and CCDC8.1–5 CUL7. Abnormal IGFBP2 andIGFBP5 mRNA levels in two patients with OBSL1 mutations, suggesting that OBSL1 modulates the 1.4 OMIM# of the gene(s) expression of IGFBP proteins. CCDC8: microsatellites analysis 609577 (CUL7), 610991 (OBSL1) and 614145 (CCDC8). at the locus (19q13.2-q13.32). CCDC8, 1-BP DUP, 612G and CCDC8, 1-BP. -
Increased Expression of Dedicator-Cytokinesis-10, Caspase
Agirrezabal et al. Multiple Sclerosis and Demyelinating Disorders (2016) 1:7 Multiple Sclerosis and DOI 10.1186/s40893-016-0009-8 Demyelinating Disorders RESEARCH ARTICLE Open Access Increased expression of dedicator- cytokinesis-10, caspase-2 and Synaptotagmin-like 2 is associated with clinical disease activity in multiple sclerosis Ion Agirrezabal1, Ricardo Palacios1, Beatriz Moreno1, Jorge Sepulcre2, Alice Abernathy1, Albert Saiz1, Sara Llufriu1, Manuel Comabella3, Xavier Montalban3, Antonio Martinez4, David Arteta4 and Pablo Villoslada1,5* Abstract Background: We aim to identify differentially expressed genes (DEGs) and its pathways associated with clinical activity of relapsing–remitting Multiple Sclerosis (RRMS). Methods: We screened DEG in blood samples from patients with clinically stable or active RRMS (≥2 relapses or increase in ≥1 point in the EDSS (due to relapses) in 2 years follow-up), and healthy controls using DNA arrays. The DEGs identified were validated by RT-PCR in a prospective cohort of MS patients. We used Gene Ontology (GO) analysis for identifying the associated pathways and Jaspar database for identifying the associated transcriptions factors. Results: We identified 45 DEG between the three groups (stable RRMS, active RRMS and control), being 14 of them significantly different between stable and active RRMS. We validated 14 out of the 45 DEG in the second cohort, eight out of the 14 being differentially expressed between active and stable patients (ARHGEF7, CASP2, DOCK10, DSP, ITPR1, KLDHC5, RBBP4, SYTL2). We found an overrepresentation of several pathways associated with lymphocyte activation. The analysis of regulatory networks identified the gene triplet of Dedicator of Cytokinesis-10 (DOCK10) – Caspase-2 (CASP2) - Synaptotagmin-like 2 (SYTL2) as being co-regulated by common transcription factors, pointing to lymphocyte activation pathways associated with disease activity. -
Identification and Validation of Methylation-Driven Genes Prognostic Signature for Recurrence of Laryngeal Squamous Cell Carcino
Cui et al. Cancer Cell Int (2020) 20:472 https://doi.org/10.1186/s12935-020-01567-3 Cancer Cell International PRIMARY RESEARCH Open Access Identifcation and validation of methylation-driven genes prognostic signature for recurrence of laryngeal squamous cell carcinoma by integrated bioinformatics analysis Jie Cui3†, Liping Wang2†, Waisheng Zhong4†, Zhen Chen5, Jie Chen4*, Hong Yang3* and Genglong Liu1* Abstract Background: Recurrence remains a major obstacle to long-term survival of laryngeal squamous cell carcinoma (LSCC). We conducted a genome-wide integrated analysis of methylation and the transcriptome to establish methyla- tion-driven genes prognostic signature (MDGPS) to precisely predict recurrence probability and optimize therapeutic strategies for LSCC. Methods: LSCC DNA methylation datasets and RNA sequencing (RNA-seq) dataset were acquired from the Cancer Genome Atlas (TCGA). MethylMix was applied to detect DNA methylation-driven genes (MDGs). By univariate and multivariate Cox regression analyses, fve genes of DNA MDGs was developed a recurrence-free survival (RFS)-related MDGPS. The predictive accuracy and clinical value of the MDGPS were evaluated by receiver operating characteristic (ROC) and decision curve analysis (DCA), and compared with TNM stage system. Additionally, prognostic value of MDGPS was validated by external Gene Expression Omnibus (GEO) database. According to 5 MDGs, the candidate small molecules for LSCC were screen out by the CMap database. To strengthen the bioinformatics analysis results, 30 pairs of clinical samples were evaluated by digoxigenin-labeled chromogenic in situ hybridization (CISH). Results: A total of 88 DNA MDGs were identifed, and fve RFS-related MDGs (LINC01354, CCDC8, PHYHD1, MAGEB2 and ZNF732) were chosen to construct a MDGPS. -
Human S100A4 (P9ka) Induces the Metastatic Phenotype Upon Benign Tumour Cells
Oncogene (1998) 17, 465 ± 473 1998 Stockton Press All rights reserved 0950 ± 9232/98 $12.00 http://www.stockton-press.co.uk/onc Human S100A4 (p9Ka) induces the metastatic phenotype upon benign tumour cells Bryony H Lloyd, Angela Platt-Higgins, Philip S Rudland and Roger Barraclough School of Biological Sciences, University of Liverpool, PO Box 147, Liverpool, L69 7ZB, UK The rodent S100-related calcium-binding protein, strengthened by the observation that transgenic mice, S100A4 induces metastasis in non-metastatic rat and expressing elevated levels of S100A4 (p9Ka) from 17 mouse benign mammary cells and co-operates with additional, position-independent rat S100A4 trans- benign-tumour-inducing changes in two transgenic mouse genes, fail to show any detectable phenotype (Davies, models, to yield metastatic mammary tumours. Co- 1993). When these mice are mated with transgenic mice transfection of the human gene for S100A4 with containing additional copies of the activated rodent c- pSV2neo into the benign rat mammary cell line, Rama erbB-2 oncogene, neu, under the control of the MMTV 37, yielded cells which expressed a low level of the LTR (Bouchard et al., 1989), ospring inheriting the endogenous S100A4 mRNA, and either high or neu oncogene suer sporadic mammary tumours after undetectable levels of human S100A4 mRNA. The cells 12 ± 14 months of repeated mating. In contrast which expressed a high level of human S100A4 mRNA ospring inheriting both neu and S100A4 transgenes induced metastasis in the benign rat mammary cell line show an elevated incidence of primary tumours, and, in Rama 37 in an in vivo assay, whereas the cells which addition, metastases in the lungs which account for up expressed an undetectable level of human S100A4 did to 24% of the total lung area (Davies et al., 1996). -
Experimental Validation of the Regulated Expression of Large Numbers of Non-Coding Rnas from the Mouse Genome
Downloaded from genome.cshlp.org on September 30, 2021 - Published by Cold Spring Harbor Laboratory Press Article Experimental validation of the regulated expression of large numbers of non-coding RNAs from the mouse genome Timothy Ravasi,1,4,5 Harukazu Suzuki,2,4 Ken C. Pang,1,3,4 Shintaro Katayama,2,4 Masaaki Furuno,2,4,6 Rie Okunishi,2 Shiro Fukuda,2 Kelin Ru,1 Martin C. Frith,1,2 M. Milena Gongora,1 Sean M. Grimmond,1 David A. Hume,1 Yoshihide Hayashizaki,2 and John S. Mattick1,7 1ARC Special Research Centre for Functional and Applied Genomics, Institute for Molecular Bioscience, University of Queensland, Brisbane QLD 4072, Australia; 2Laboratory for Genome Exploration Research Group, RIKEN Genomic Science Center, RIKEN Yokohama Institute, Suehiro-cho, Tsurumi-ku, Yokohama, Kanagawa, 230-0045, Japan; 3T Cell Laboratory, Ludwig Institute for Cancer Research, Austin & Repatriation Medical Centre, Heidelberg VIC 3084, Australia Recent large-scale analyses of mainly full-length cDNA libraries generated from a variety of mouse tissues indicated that almost half of all representative cloned sequences did not contain an apparent protein-coding sequence, and were putatively derived from non-protein-coding RNA (ncRNA) genes. However, many of these clones were singletons and the majority were unspliced, raising the possibility that they may be derived from genomic DNA or unprocessed pre-mRNA contamination during library construction, or alternatively represent nonspecific “transcriptional noise.” Here we show, using reverse transcriptase-dependent PCR, microarray, and Northern blot analyses, that many of these clones were derived from genuine transcripts of unknown function whose expression appears to be regulated. -
Biological and Prognostic Significance of Chromosome 5Q Deletions in Myeloid Malignancies Aristoteles A.N
Review Biological and Prognostic Significance of Chromosome 5q Deletions in Myeloid Malignancies Aristoteles A.N. Giagounidis,1Ulrich Germing,2 and Carlo Aul1 Abstract The presence of del(5q), either as the sole karyotypic abnormality or as part of a more complex karyotype, has distinct clinical implications for myelodysplastic syndromes (MDS) and acute myeloid leukemia. The 5qÀ syndrome, a subtype of low-riskMDS, is characterized by an isolated 5q deletion and <5% blasts in the bone marrow and can serve as a useful model for studying the role of 5q deletions in the pathogenesis and prognosis of myeloid malignancies. Recent clinical results with lenalidomide, an oral immunomodulatory drug, have shown durable erythroid responses, including transfusion independence and complete cytogenetic remissions in patients with del(5q) MDS with or without additional chromosomal abnormalities. These results indicate that lenalidomide can overcome the pathogenic effect of 5q deletion in MDS and restore bone marrow balance. The data provide important new insights into the pathobiology of 5q chromo- somal deletions in myeloid malignancies. Cytogenetic abnormalities are detected in the bone marrow of preponderance, refractory macrocytic anemia, normal or high over 50% of patients diagnosed with primary myelodysplastic platelet counts, hypolobulated megakaryocytes, and modest syndromes (MDS) or myeloid leukemias, and up to 80% of leukopenia (11, 14, 17). The prognosis is favorable in 5qÀ patients with secondary or therapy-related MDS (1, 2). These syndrome with relatively low risk of transformation to AML abnormalities can be characterized as being balanced or (11, 18). Although the limits of 5q deletions vary among unbalanced (3, 4). Balanced cytogenetic abnormalities include patients with 5qÀ syndrome, the most frequent deletion is reciprocal translocations, inversions, and insertions (3, 5, 6). -
Molecular Effects of Isoflavone Supplementation Human Intervention Studies and Quantitative Models for Risk Assessment
Molecular effects of isoflavone supplementation Human intervention studies and quantitative models for risk assessment Vera van der Velpen Thesis committee Promotors Prof. Dr Pieter van ‘t Veer Professor of Nutritional Epidemiology Wageningen University Prof. Dr Evert G. Schouten Emeritus Professor of Epidemiology and Prevention Wageningen University Co-promotors Dr Anouk Geelen Assistant professor, Division of Human Nutrition Wageningen University Dr Lydia A. Afman Assistant professor, Division of Human Nutrition Wageningen University Other members Prof. Dr Jaap Keijer, Wageningen University Dr Hubert P.J.M. Noteborn, Netherlands Food en Consumer Product Safety Authority Prof. Dr Yvonne T. van der Schouw, UMC Utrecht Dr Wendy L. Hall, King’s College London This research was conducted under the auspices of the Graduate School VLAG (Advanced studies in Food Technology, Agrobiotechnology, Nutrition and Health Sciences). Molecular effects of isoflavone supplementation Human intervention studies and quantitative models for risk assessment Vera van der Velpen Thesis submitted in fulfilment of the requirements for the degree of doctor at Wageningen University by the authority of the Rector Magnificus Prof. Dr M.J. Kropff, in the presence of the Thesis Committee appointed by the Academic Board to be defended in public on Friday 20 June 2014 at 13.30 p.m. in the Aula. Vera van der Velpen Molecular effects of isoflavone supplementation: Human intervention studies and quantitative models for risk assessment 154 pages PhD thesis, Wageningen University, Wageningen, NL (2014) With references, with summaries in Dutch and English ISBN: 978-94-6173-952-0 ABSTRact Background: Risk assessment can potentially be improved by closely linked experiments in the disciplines of epidemiology and toxicology. -
Absence of S100A4 in the Mouse Lens Induces an Aberrant Retina-Specific Differentiation Program and Cataract
www.nature.com/scientificreports OPEN Absence of S100A4 in the mouse lens induces an aberrant retina‑specifc diferentiation program and cataract Rupalatha Maddala1*, Junyuan Gao2, Richard T. Mathias2, Tylor R. Lewis1, Vadim Y. Arshavsky1,3, Adriana Levine4, Jonathan M. Backer4,5, Anne R. Bresnick4 & Ponugoti V. Rao1,3* S100A4, a member of the S100 family of multifunctional calcium‑binding proteins, participates in several physiological and pathological processes. In this study, we demonstrate that S100A4 expression is robustly induced in diferentiating fber cells of the ocular lens and that S100A4 (−/−) knockout mice develop late‑onset cortical cataracts. Transcriptome profling of lenses from S100A4 (−/−) mice revealed a robust increase in the expression of multiple photoreceptor‑ and Müller glia‑specifc genes, as well as the olfactory sensory neuron‑specifc gene, S100A5. This aberrant transcriptional profle is characterized by corresponding increases in the levels of proteins encoded by the aberrantly upregulated genes. Ingenuity pathway network and curated pathway analyses of diferentially expressed genes in S100A4 (−/−) lenses identifed Crx and Nrl transcription factors as the most signifcant upstream regulators, and revealed that many of the upregulated genes possess promoters containing a high‑density of CpG islands bearing trimethylation marks at histone H3K27 and/or H3K4, respectively. In support of this fnding, we further documented that S100A4 (−/−) knockout lenses have altered levels of trimethylated H3K27 and H3K4. Taken together, -
Analysis of the Indacaterol-Regulated Transcriptome in Human Airway
Supplemental material to this article can be found at: http://jpet.aspetjournals.org/content/suppl/2018/04/13/jpet.118.249292.DC1 1521-0103/366/1/220–236$35.00 https://doi.org/10.1124/jpet.118.249292 THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS J Pharmacol Exp Ther 366:220–236, July 2018 Copyright ª 2018 by The American Society for Pharmacology and Experimental Therapeutics Analysis of the Indacaterol-Regulated Transcriptome in Human Airway Epithelial Cells Implicates Gene Expression Changes in the s Adverse and Therapeutic Effects of b2-Adrenoceptor Agonists Dong Yan, Omar Hamed, Taruna Joshi,1 Mahmoud M. Mostafa, Kyla C. Jamieson, Radhika Joshi, Robert Newton, and Mark A. Giembycz Departments of Physiology and Pharmacology (D.Y., O.H., T.J., K.C.J., R.J., M.A.G.) and Cell Biology and Anatomy (M.M.M., R.N.), Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada Received March 22, 2018; accepted April 11, 2018 Downloaded from ABSTRACT The contribution of gene expression changes to the adverse and activity, and positive regulation of neutrophil chemotaxis. The therapeutic effects of b2-adrenoceptor agonists in asthma was general enriched GO term extracellular space was also associ- investigated using human airway epithelial cells as a therapeu- ated with indacaterol-induced genes, and many of those, in- tically relevant target. Operational model-fitting established that cluding CRISPLD2, DMBT1, GAS1, and SOCS3, have putative jpet.aspetjournals.org the long-acting b2-adrenoceptor agonists (LABA) indacaterol, anti-inflammatory, antibacterial, and/or antiviral activity. Numer- salmeterol, formoterol, and picumeterol were full agonists on ous indacaterol-regulated genes were also induced or repressed BEAS-2B cells transfected with a cAMP-response element in BEAS-2B cells and human primary bronchial epithelial cells by reporter but differed in efficacy (indacaterol $ formoterol . -
Convergent Functional Genomics of Schizophrenia: from Comprehensive Understanding to Genetic Risk Prediction
Molecular Psychiatry (2012) 17, 887 -- 905 & 2012 Macmillan Publishers Limited All rights reserved 1359-4184/12 www.nature.com/mp IMMEDIATE COMMUNICATION Convergent functional genomics of schizophrenia: from comprehensive understanding to genetic risk prediction M Ayalew1,2,9, H Le-Niculescu1,9, DF Levey1, N Jain1, B Changala1, SD Patel1, E Winiger1, A Breier1, A Shekhar1, R Amdur3, D Koller4, JI Nurnberger1, A Corvin5, M Geyer6, MT Tsuang6, D Salomon7, NJ Schork7, AH Fanous3, MC O’Donovan8 and AB Niculescu1,2 We have used a translational convergent functional genomics (CFG) approach to identify and prioritize genes involved in schizophrenia, by gene-level integration of genome-wide association study data with other genetic and gene expression studies in humans and animal models. Using this polyevidence scoring and pathway analyses, we identify top genes (DISC1, TCF4, MBP, MOBP, NCAM1, NRCAM, NDUFV2, RAB18, as well as ADCYAP1, BDNF, CNR1, COMT, DRD2, DTNBP1, GAD1, GRIA1, GRIN2B, HTR2A, NRG1, RELN, SNAP-25, TNIK), brain development, myelination, cell adhesion, glutamate receptor signaling, G-protein-- coupled receptor signaling and cAMP-mediated signaling as key to pathophysiology and as targets for therapeutic intervention. Overall, the data are consistent with a model of disrupted connectivity in schizophrenia, resulting from the effects of neurodevelopmental environmental stress on a background of genetic vulnerability. In addition, we show how the top candidate genes identified by CFG can be used to generate a genetic risk prediction score (GRPS) to aid schizophrenia diagnostics, with predictive ability in independent cohorts. The GRPS also differentiates classic age of onset schizophrenia from early onset and late-onset disease.