DOCSLIB.ORG

Exploratory Locomotion, a Predictor of Addiction Vulnerability, Is Oligogenic in Rats Selected for This Phenotype

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Exploratory Locomotion, a Predictor of Addiction Vulnerability, Is Oligogenic in Rats Selected for This Phenotype Exploratory locomotion, a predictor of addiction vulnerability, is oligogenic in rats selected for this phenotype Zhifeng Zhoua,1, Peter Blandinob,c,1, Qiaoping Yuana, Pei-Hong Shena, Colin A. Hodgkinsona, Matti Virkkunend, Stanley J. Watsonb,c, Huda Akilb,c,2, and David Goldmana,2 aLaboratory of Neurogenetics, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD 20852; bMolecular and Behavioral Neuroscience Institute, University of Michigan, Ann Arbor, MI 48109; cDepartment of Psychiatry, University of Michigan, Ann Arbor, MI 48109; and dDepartment of Psychiatry, University of Helsinki, 00014 Helsinki, Finland Contributed by Huda Akil, May 10, 2019 (sent for review November 30, 2018; reviewed by Elissa J. Chesler and Robert Hitzemann) Artificially selected model organisms can reveal hidden features of resilience, the search for genetic components that influence re- the genetic architecture of the complex disorders that they model. sponse to novelty and vulnerability to addiction has proven Addictions are disease phenotypes caused by different intermedi- challenging, with only a fraction of the genetic variance in ad- ate phenotypes and pathways and thereby are potentially highly diction liability accounted for by genome-wide association stud- polygenic. High responder (bHR) and low responder (bLR) rat lines ies (GWAS). This may be due to multiple confounding factors have been selectively bred (b) for exploratory locomotion (EL), a including genetic heterogeneity, small effect sizes of each gene/ behavioral phenotype correlated with novelty-seeking, impulsive locus, and phenotypic heterogeneity resulting from variable response to reward, and vulnerability to addiction, and is inversely causes for use emergent at different stages of addiction and correlated with spontaneous anxiety and depression-like behav- normal development. The failure to identify loci via GWAS has iors. The rapid response to selection indicates loci of large effect been interpreted to mean that behavioral traits are polygenic and for EL. Using exome sequencing of HR and LR rats, we identified has led to speculation that behavioral diseases are omnigenic and alleles in gene-coding regions that segregate between the two caused by alleles of infinitesimal effect (5). As well as implicating lines. Quantitative trait locus (QTL) analysis in F2 rats derived from novel genes, addiction GWAS have succeeded in recovering NEUROSCIENCE a bHR × bLR intercross confirmed that these regions harbored several genes previously implicated by study of genes and path- genes affecting EL. The combined effects of the seven genome- ways known to be important in addiction, for example ADH1B wide significant QTLs accounted for approximately one-third of and ALDH2 for alcoholism and CHRNA3 for nicotine addiction the total variance in EL, and two-thirds of the variance attributable (6–8). Cellular and molecular studies of addictions, including to genetic factors, consistent with an oligogenic architecture of EL studies of the transcriptome, have identified diverse changes estimated both from the phenotypic distribution of F2 animals and rapid response to selection. Genetic association in humans linked Significance APBA2, the ortholog of the gene at the center of the strongest QTL, with substance use disorders and related behavioral pheno- While addiction disorders have a genetic basis, the expected types. Our finding is also convergent with molecular and animal number of genes contributing to them is large, hence their behavioral studies implicating Apba2 in locomotion. These results classification as polygenic disorders. Animal models can enable provide multilevel evidence for genes/loci influencing EL. They discovery of genes of larger effect by targeting specific com- shed light on the genetic architecture of oligogenicity in animals ponents of genetic vulnerability. High responder and low re- artificially selected for a phenotype modeling a more complex sponder rats were selectively bred based on exploratory disorder in humans. locomotion (EL) in a novel environment, a predictor of drug- seeking behavior. Using exome sequencing and quantitative addiction | genetics | locomotion | novelty seeking | oligogenic trait locus analysis, we identified seven genome-wide signifi- cant loci accounting for approximately one-third of total vari- ddictions are common, etiologically complex disorders that ance and two-thirds of genetic variance in EL. We found Alead to diverse morbid outcomes and early mortality. En- convergent evidence for a role of APBA2 in humans. Thus, EL is vironmental and genetic factors play important roles in vulner- oligogenic, being strongly influenced by a limited number of ability and resilience to addiction, and the unfolding of the loci of large effect size. addiction process (1, 2). Although addictive disorders, defined in the Diagnostic and Statistical Manual of Mental Disorders, 5th Author contributions: S.J.W., H.A., and D.G. designed research; Z.Z. and P.B. performed Edition (DSM5) as use disorders, are contingent on availability research; P.B., C.A.H., S.J.W., H.A., and D.G. contributed new reagents/analytic tools; Z.Z., and use of an addictive agent, people are differentially vulner- P.B., Q.Y., P.-H.S., M.V., and D.G. analyzed data; and Z.Z., C.A.H., H.A., and D.G. wrote the paper. able at multiple stages of the cycle of addiction, including the Reviewers: E.J.C., The Jackson Laboratory; and R.H., Oregon Health & Science University initial propensity to use, transition from use to abuse, long-term and Portland VA Medical Center. addiction, and relapse (3). Genetic variation influences risks, The authors declare no conflict of interest. responses, and trajectories of addiction. Response to novelty and × This open access article is distributed under Creative Commons Attribution-NonCommercial- novelty seeking play a particularly important role in gene en- NoDerivatives License 4.0 (CC BY-NC-ND). vironment correlation and interaction, because exposure and use Data deposition: Sequences of the bHR/bLR exomes have been deposited in NCBI as a set the stage for addiction. Bioproject (accession no. PRJNA521139). Measured as extraversion, novelty seeking and response to 1Z.Z. and P.B. contributed equally to this work. 2 = novel environments is moderately heritable (h 0.4) in people. 2To whom correspondence may be addressed. Email: [email protected] or David.Goldman@ Addictions themselves are also moderately to highly heritable, as nih.hhs.gov. observed in large samples of twins representative of populations This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. (4). However, despite the discovery of causal variants at several 1073/pnas.1820410116/-/DCSupplemental. genes involved in drug metabolism, receptor/signaling and stress Published online June 10, 2019. www.pnas.org/cgi/doi/10.1073/pnas.1820410116 PNAS | June 25, 2019 | vol. 116 | no. 26 | 13107–13115 Downloaded by guest on September 26, 2021 associated with neural adaptive processes (9–11). Perturbations Results of molecular components critical for neurotransmission such as Exome Sequencing Identifies Genetic Variants Segregating between glutamatergic, GABAergic, and dopaminergic systems have been bHR and bLR Rats. Broad sense heritability (H2) of EL was 0.489, recognized (12–15). However, the main successes in the discov- calculated based on variance of this phenotype in bHR and bLR ery of processes involved in addiction have been in under- F0, F1, and F2 offspring (SI Appendix, Fig. S1). Therefore, EL is standing intermediate mechanisms and tertiary consequences, substantially heritable and the bHR and bLR rats are potentially rather than primary causes. a model for identification of loci influencing novelty response. By Animal models enable well-controlled designs to minimize applying Wright’s estimator (23, 24) to the means and variances confounding factors. Animals selectively bred for targeted phe- of locomotor scores in bHR and bLR and variance in F2 off- notypes are of particular value for the identification of alleles spring, we calculated that the minimum number of loci that may naturally occurring in those species (16, 17) because selection contribute to total variance in EL is 15.7 (SI Appendix, Fig. S1). enriches and even genetically fixes alleles that influence the EL in bHR/LR might therefore be regarded as oligogenic, but phenotype. In such models, genetic, phenotypic, and environ- not omnigenic, a hypothesis potentially resolvable by discovery of mental complexity can be reduced, enabling detection of loci loci and measurement of their individual and joint contributions. with relatively large effect sizes. For example, two stop codons We performed exome sequencing in 12 bHR and 12 bLR F0 influencing alcohol preference together account for 6% of the animals that were the product of 18 generations of selection and total variance for this phenotype and were genetically fixed by 37 generations of breeding, identifying genetic variants in the selection in alcohol-preferring (P) and nonpreferring (NP) rats gene-coding regions that segregate between bHR and bLR lines (18). Fixation of the Grm2 stop codon, which is either common (25). The exome sequencing generated adequate coverage (av- or genetically fixed in outbred Wistar rats from different sources, erage 86×, across the 50-Mb exome target) and identified a total leads to uncompensated loss of metabotropic glutamate receptor of 110,172 single nucleotide variants
Load more

Recommended publications
  • Genome-Wide Analysis of Host-Chromosome Binding Sites For
    Lu et al. Virology Journal 2010, 7:262 http://www.virologyj.com/content/7/1/262 RESEARCH Open Access Genome-wide analysis of host-chromosome binding sites for Epstein-Barr Virus Nuclear Antigen 1 (EBNA1) Fang Lu1, Priyankara Wikramasinghe1, Julie Norseen1,2, Kevin Tsai1, Pu Wang1, Louise Showe1, Ramana V Davuluri1, Paul M Lieberman1* Abstract The Epstein-Barr Virus (EBV) Nuclear Antigen 1 (EBNA1) protein is required for the establishment of EBV latent infection in proliferating B-lymphocytes. EBNA1 is a multifunctional DNA-binding protein that stimulates DNA replication at the viral origin of plasmid replication (OriP), regulates transcription of viral and cellular genes, and tethers the viral episome to the cellular chromosome. EBNA1 also provides a survival function to B-lymphocytes, potentially through its ability to alter cellular gene expression. To better understand these various functions of EBNA1, we performed a genome-wide analysis of the viral and cellular DNA sites associated with EBNA1 protein in a latently infected Burkitt lymphoma B-cell line. Chromatin-immunoprecipitation (ChIP) combined with massively parallel deep-sequencing (ChIP-Seq) was used to identify cellular sites bound by EBNA1. Sites identified by ChIP- Seq were validated by conventional real-time PCR, and ChIP-Seq provided quantitative, high-resolution detection of the known EBNA1 binding sites on the EBV genome at OriP and Qp. We identified at least one cluster of unusually high-affinity EBNA1 binding sites on chromosome 11, between the divergent FAM55 D and FAM55B genes. A con- sensus for all cellular EBNA1 binding sites is distinct from those derived from the known viral binding sites, sug- gesting that some of these sites are indirectly bound by EBNA1.
    [Show full text]
  • Evidence for Differential Alternative Splicing in Blood of Young Boys With
    Stamova et al. Molecular Autism 2013, 4:30 http://www.molecularautism.com/content/4/1/30 RESEARCH Open Access Evidence for differential alternative splicing in blood of young boys with autism spectrum disorders Boryana S Stamova1,2,5*, Yingfang Tian1,2,4, Christine W Nordahl1,3, Mark D Shen1,3, Sally Rogers1,3, David G Amaral1,3 and Frank R Sharp1,2 Abstract Background: Since RNA expression differences have been reported in autism spectrum disorder (ASD) for blood and brain, and differential alternative splicing (DAS) has been reported in ASD brains, we determined if there was DAS in blood mRNA of ASD subjects compared to typically developing (TD) controls, as well as in ASD subgroups related to cerebral volume. Methods: RNA from blood was processed on whole genome exon arrays for 2-4–year-old ASD and TD boys. An ANCOVA with age and batch as covariates was used to predict DAS for ALL ASD (n=30), ASD with normal total cerebral volumes (NTCV), and ASD with large total cerebral volumes (LTCV) compared to TD controls (n=20). Results: A total of 53 genes were predicted to have DAS for ALL ASD versus TD, 169 genes for ASD_NTCV versus TD, 1 gene for ASD_LTCV versus TD, and 27 genes for ASD_LTCV versus ASD_NTCV. These differences were significant at P <0.05 after false discovery rate corrections for multiple comparisons (FDR <5% false positives). A number of the genes predicted to have DAS in ASD are known to regulate DAS (SFPQ, SRPK1, SRSF11, SRSF2IP, FUS, LSM14A). In addition, a number of genes with predicted DAS are involved in pathways implicated in previous ASD studies, such as ROS monocyte/macrophage, Natural Killer Cell, mTOR, and NGF signaling.
    [Show full text]
  • Proteomics Provides Insights Into the Inhibition of Chinese Hamster V79
    www.nature.com/scientificreports OPEN Proteomics provides insights into the inhibition of Chinese hamster V79 cell proliferation in the deep underground environment Jifeng Liu1,2, Tengfei Ma1,2, Mingzhong Gao3, Yilin Liu4, Jun Liu1, Shichao Wang2, Yike Xie2, Ling Wang2, Juan Cheng2, Shixi Liu1*, Jian Zou1,2*, Jiang Wu2, Weimin Li2 & Heping Xie2,3,5 As resources in the shallow depths of the earth exhausted, people will spend extended periods of time in the deep underground space. However, little is known about the deep underground environment afecting the health of organisms. Hence, we established both deep underground laboratory (DUGL) and above ground laboratory (AGL) to investigate the efect of environmental factors on organisms. Six environmental parameters were monitored in the DUGL and AGL. Growth curves were recorded and tandem mass tag (TMT) proteomics analysis were performed to explore the proliferative ability and diferentially abundant proteins (DAPs) in V79 cells (a cell line widely used in biological study in DUGLs) cultured in the DUGL and AGL. Parallel Reaction Monitoring was conducted to verify the TMT results. γ ray dose rate showed the most detectable diference between the two laboratories, whereby γ ray dose rate was signifcantly lower in the DUGL compared to the AGL. V79 cell proliferation was slower in the DUGL. Quantitative proteomics detected 980 DAPs (absolute fold change ≥ 1.2, p < 0.05) between V79 cells cultured in the DUGL and AGL. Of these, 576 proteins were up-regulated and 404 proteins were down-regulated in V79 cells cultured in the DUGL. KEGG pathway analysis revealed that seven pathways (e.g.
    [Show full text]
  • APBA2 Antibody A
    C 0 2 - t APBA2 Antibody a e r o t S Orders: 877-616-CELL (2355) [email protected] Support: 877-678-TECH (8324) 3 9 Web: [email protected] 5 www.cellsignal.com 8 # 3 Trask Lane Danvers Massachusetts 01923 USA For Research Use Only. Not For Use In Diagnostic Procedures. Applications: Reactivity: Sensitivity: MW (kDa): Source: UniProt ID: Entrez-Gene Id: WB, IP M R Endogenous 135 Rabbit Q99767 321 Product Usage Information Application Dilution Western Blotting 1:1000 Immunoprecipitation 1:50 Storage Supplied in 10 mM sodium HEPES (pH 7.5), 150 mM NaCl, 100 µg/ml BSA and 50% glycerol. Store at –20°C. Do not aliquot the antibody. Specificity / Sensitivity APBA2 Antibody recognizes endogenous levels of total APBA2 protein. Species Reactivity: Mouse, Rat Species predicted to react based on 100% sequence homology: Human Source / Purification Polyclonal antibodies are produced by immunizing animals with a synthetic peptide corresponding to residues surrounding Phe300 of human APBA2 protein. Antibodies are purified by protein A and peptide affinity chromatography. Background Amyloid β A4 precursor protein-binding family A member 2 (APBA2) is a neuronal adaptor protein that interacts with the amyloid β precursor protein (APP) (1). The amyloid β-protein (Aβ) is the principal component of amyloid plaques, a pathological hallmark of Alzheimer’s disease (2). APBA2 has been shown to stabilize APP metabolism and suppress the secretion of Aβ (3). APBA2 mediates interaction between APP and the neural type I membrane protein Alcadein (Alc) by linking their cytoplasmic domains, thereby forming a tripartite complex of the three proteins in neurons (4).
    [Show full text]
  • 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.
    [Show full text]
  • Aneuploidy: Using Genetic Instability to Preserve a Haploid Genome?
    Health Science Campus FINAL APPROVAL OF DISSERTATION Doctor of Philosophy in Biomedical Science (Cancer Biology) Aneuploidy: Using genetic instability to preserve a haploid genome? Submitted by: Ramona Ramdath In partial fulfillment of the requirements for the degree of Doctor of Philosophy in Biomedical Science Examination Committee Signature/Date Major Advisor: David Allison, M.D., Ph.D. Academic James Trempe, Ph.D. Advisory Committee: David Giovanucci, Ph.D. Randall Ruch, Ph.D. Ronald Mellgren, Ph.D. Senior Associate Dean College of Graduate Studies Michael S. Bisesi, Ph.D. Date of Defense: April 10, 2009 Aneuploidy: Using genetic instability to preserve a haploid genome? Ramona Ramdath University of Toledo, Health Science Campus 2009 Dedication I dedicate this dissertation to my grandfather who died of lung cancer two years ago, but who always instilled in us the value and importance of education. And to my mom and sister, both of whom have been pillars of support and stimulating conversations. To my sister, Rehanna, especially- I hope this inspires you to achieve all that you want to in life, academically and otherwise. ii Acknowledgements As we go through these academic journeys, there are so many along the way that make an impact not only on our work, but on our lives as well, and I would like to say a heartfelt thank you to all of those people: My Committee members- Dr. James Trempe, Dr. David Giovanucchi, Dr. Ronald Mellgren and Dr. Randall Ruch for their guidance, suggestions, support and confidence in me. My major advisor- Dr. David Allison, for his constructive criticism and positive reinforcement.
    [Show full text]
  • Expression Analysis of Circular Rnas in Young and Sexually Mature Boar Testes
    animals Article Expression Analysis of Circular RNAs in Young and Sexually Mature Boar Testes Fei Zhang 1,2,† , Xiaodong Zhang 1,†, Wei Ning 1, Xiangdong Zhang 1, Zhenyuan Ru 1, Shiqi Wang 1, Mei Sheng 1, Junrui Zhang 1, Xueying Zhang 1, Haiqin Luo 1, Xin Wang 1, Zubing Cao 1,* and Yunhai Zhang 1,* 1 Anhui Province Key Laboratory of Local Livestock and Poultry, Genetical Resource Conservation and Breeding, College of Animal Science and Technology, Anhui Agricultural University, Hefei 230036, China; [email protected] (F.Z.); [email protected] (X.Z.); [email protected] (W.N.); [email protected] (X.Z.); [email protected] (Z.R.); [email protected] (S.W.); [email protected] (M.S.); [email protected] (J.Z.); [email protected] (X.Z.); [email protected] (H.L.); [email protected] (X.W.) 2 School of Life Sciences, Anhui Agricultural University, Hefei 230036, China * Correspondence: [email protected] (Z.C.); [email protected] (Y.Z.); Tel.: +86-551-6578-6357 (Y.Z.) † These authors contributed equally to this study. Simple Summary: Circular RNAs are novel long non-coding RNA involved in the regulation of gene expression. Recently, the expression of circRNAs was characterized in testes of humans and bulls. However, the profiling of circRNAs and their potential biological functions in boar testicular development are yet to be known. In this study we characterized expression and biological roles of circRNAs in piglet (30 d) and adult (210 d) boar testes by high-throughput sequencing. We identified a large number of circRNAs during testicular development, of which 2326 circRNAs exhibited a significantly differential expression.
    [Show full text]
  • Integrative Bulk and Single-Cell Profiling of Premanufacture T-Cell Populations Reveals Factors Mediating Long-Term Persistence of CAR T-Cell Therapy
    Published OnlineFirst April 5, 2021; DOI: 10.1158/2159-8290.CD-20-1677 RESEARCH ARTICLE Integrative Bulk and Single-Cell Profiling of Premanufacture T-cell Populations Reveals Factors Mediating Long-Term Persistence of CAR T-cell Therapy Gregory M. Chen1, Changya Chen2,3, Rajat K. Das2, Peng Gao2, Chia-Hui Chen2, Shovik Bandyopadhyay4, Yang-Yang Ding2,5, Yasin Uzun2,3, Wenbao Yu2, Qin Zhu1, Regina M. Myers2, Stephan A. Grupp2,5, David M. Barrett2,5, and Kai Tan2,3,5 Downloaded from cancerdiscovery.aacrjournals.org on October 1, 2021. © 2021 American Association for Cancer Research. Published OnlineFirst April 5, 2021; DOI: 10.1158/2159-8290.CD-20-1677 ABSTRACT The adoptive transfer of chimeric antigen receptor (CAR) T cells represents a breakthrough in clinical oncology, yet both between- and within-patient differences in autologously derived T cells are a major contributor to therapy failure. To interrogate the molecular determinants of clinical CAR T-cell persistence, we extensively characterized the premanufacture T cells of 71 patients with B-cell malignancies on trial to receive anti-CD19 CAR T-cell therapy. We performed RNA-sequencing analysis on sorted T-cell subsets from all 71 patients, followed by paired Cellular Indexing of Transcriptomes and Epitopes (CITE) sequencing and single-cell assay for transposase-accessible chromatin sequencing (scATAC-seq) on T cells from six of these patients. We found that chronic IFN signaling regulated by IRF7 was associated with poor CAR T-cell persistence across T-cell subsets, and that the TCF7 regulon not only associates with the favorable naïve T-cell state, but is maintained in effector T cells among patients with long-term CAR T-cell persistence.
    [Show full text]
  • Gene Ontology Functional Annotations and Pleiotropy
    Network based analysis of genetic disease associations Sarah Gilman 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 2014 © 2013 Sarah Gilman All Rights Reserved ABSTRACT Network based analysis of genetic disease associations Sarah Gilman Despite extensive efforts and many promising early findings, genome-wide association studies have explained only a small fraction of the genetic factors contributing to common human diseases. There are many theories about where this “missing heritability” might lie, but increasingly the prevailing view is that common variants, the target of GWAS, are not solely responsible for susceptibility to common diseases and a substantial portion of human disease risk will be found among rare variants. Relatively new, such variants have not been subject to purifying selection, and therefore may be particularly pertinent for neuropsychiatric disorders and other diseases with greatly reduced fecundity. Recently, several researchers have made great progress towards uncovering the genetics behind autism and schizophrenia. By sequencing families, they have found hundreds of de novo variants occurring only in affected individuals, both large structural copy number variants and single nucleotide variants. Despite studying large cohorts there has been little recurrence among the genes implicated suggesting that many hundreds of genes may underlie these complex phenotypes. The question
    [Show full text]
  • APBA2 Blocking Peptide (CDBP5073) This Product Is for Research Use Only and Is Not Intended for Diagnostic Use
    APBA2 blocking peptide (CDBP5073) This product is for research use only and is not intended for diagnostic use. PRODUCT INFORMATION Antigen Description The protein encoded by this gene is a member of the X11 protein family. It is a neuronal adapter protein that interacts with the Alzheimer's disease amyloid precursor protein (APP). It stabilizes APP and inhibits production of proteolytic APP fragments including the A beta peptide that is deposited in the brains of Alzheimer's disease patients. This gene product is believed to be involved in signal transduction processes. It is also regarded as a putative vesicular trafficking protein in the brain that can form a complex with the potential to couple synaptic vesicle exocytosis to neuronal cell adhesion. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008] Immunogen 18 amino acids near the amino terminus of human APBA2. Nature Synthetic Expression System N/A Species Reactivity Human Conjugate Unconjugated Applications Used as a blocking peptide in immunoblotting applications. Procedure None Format Liquid Concentration 200 μg/mL Size 0.05mg Preservative None Storage -20°C ANTIGEN GENE INFORMATION Gene Name APBA2 amyloid beta (A4) precursor protein-binding, family A, member 2 [ Homo sapiens (human) ] Official Symbol APBA2 45-1 Ramsey Road, Shirley, NY 11967, USA Email: [email protected] Tel: 1-631-624-4882 Fax: 1-631-938-8221 1 © Creative Diagnostics All Rights Reserved Synonyms APBA2; amyloid beta (A4) precursor
    [Show full text]
  • UC San Diego UC San Diego Electronic Theses and Dissertations
    UC San Diego UC San Diego Electronic Theses and Dissertations Title Regulation of gene expression programs by serum response factor and megakaryoblastic leukemia 1/2 in macrophages Permalink https://escholarship.org/uc/item/8cc7d0t0 Author Sullivan, Amy Lynn Publication Date 2009 Peer reviewed|Thesis/dissertation eScholarship.org Powered by the California Digital Library University of California UNIVERSITY OF CALIFORNIA, SAN DIEGO Regulation of Gene Expression Programs by Serum Response Factor and Megakaryoblastic Leukemia 1/2 in Macrophages A dissertation submitted in partial satisfaction of the requirements for the degree Doctor of Philosophy in Biomedical Sciences by Amy Lynn Sullivan Committee in charge: Professor Christopher K. Glass, Chair Professor Stephen M. Hedrick Professor Marc R. Montminy Professor Nicholas J. Webster Professor Joseph L. Witztum 2009 Copyright Amy Lynn Sullivan, 2009 All rights reserved. The Dissertation of Amy Lynn Sullivan is approved, and it is acceptable in quality and form for publication on microfilm and electronically: ______________________________________________________________ ______________________________________________________________ ______________________________________________________________ ______________________________________________________________ ______________________________________________________________ Chair University of California, San Diego 2009 iii DEDICATION To my husband, Shane, for putting up with me through all of the long hours, last minute late nights, and for not letting me quit no matter how many times my projects fell apart. To my son, Tyler, for always making me smile and for making every day an adventure. To my gifted colleagues, for all of the thought-provoking discussions, technical help and moral support through the roller- coaster ride that has been my graduate career. To my family and friends, for all of your love and support. I couldn’t have done it without you! iv EPIGRAPH If at first you don’t succeed, try, try, again.
    [Show full text]
  • Gene Networks Activated by Specific Patterns of Action Potentials in Dorsal Root Ganglia Neurons Received: 10 August 2016 Philip R
    www.nature.com/scientificreports OPEN Gene networks activated by specific patterns of action potentials in dorsal root ganglia neurons Received: 10 August 2016 Philip R. Lee1,*, Jonathan E. Cohen1,*, Dumitru A. Iacobas2,3, Sanda Iacobas2 & Accepted: 23 January 2017 R. Douglas Fields1 Published: 03 March 2017 Gene regulatory networks underlie the long-term changes in cell specification, growth of synaptic connections, and adaptation that occur throughout neonatal and postnatal life. Here we show that the transcriptional response in neurons is exquisitely sensitive to the temporal nature of action potential firing patterns. Neurons were electrically stimulated with the same number of action potentials, but with different inter-burst intervals. We found that these subtle alterations in the timing of action potential firing differentially regulates hundreds of genes, across many functional categories, through the activation or repression of distinct transcriptional networks. Our results demonstrate that the transcriptional response in neurons to environmental stimuli, coded in the pattern of action potential firing, can be very sensitive to the temporal nature of action potential delivery rather than the intensity of stimulation or the total number of action potentials delivered. These data identify temporal kinetics of action potential firing as critical components regulating intracellular signalling pathways and gene expression in neurons to extracellular cues during early development and throughout life. Adaptation in the nervous system in response to external stimuli requires synthesis of new gene products in order to elicit long lasting changes in processes such as development, response to injury, learning, and memory1. Information in the environment is coded in the pattern of action-potential firing, therefore gene transcription must be regulated by the pattern of neuronal firing.
    [Show full text]