The Splicing Factor PQBP1 Regulates Mesodermal and Neural Development Through FGF Signaling Yasuno Iwasaki and Gerald H
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Fish Mutant, Where Is Thy Phenotype?
PERSPECTIVE Fish mutant, where is thy phenotype? Darius Balciunas* Department of Biology, Temple University, Philadelphia, Pennsylvania, United States of America * [email protected] The field of genetics emerged as a study of the inheritance of desirable or otherwise interesting traits. Mutations were characterized as recessive or dominant, assigned to complementation groups, mapped, and finally, the affected genes were identified. By default, recessive mutations could only be isolated in genes that played an important role in the biological process of inter- est, be it pea color or segmentation pattern of the fruit fly embryo. As methodologies to mutate specific genes in various model systems were developed, scien- tists began to employ reverse genetics, whereby a gene of interest is selected and a mutant is generated. Ideally, the mutant displays a phenotype that can be studied (green panels in Fig 1). Such best-case scenarios pose the danger of confirmation bias ([1] and references therein). It may therefore be prudent to validate the phenotype by engineering an independent mutant allele. This is especially straightforward in zebrafish, given that targeted mutagenesis using CRISPR/Cas9 requires relatively little effort [2±4]. In zebrafish, the phenotype may also be confirmed by performing knockdown using morpholino oligonucleotides [5±6]. a1111111111 Real experiments rarely follow best-case scenarios, and very frequently, mutants generated a1111111111 by reverse genetics fail to display overt phenotypes. Are the majority of protein-coding genes a1111111111 indeed not required, often despite a very high degree of evolutionary conservation? Genetic a1111111111 redundancy, most obviously in the form of homologous or duplicated genes, certainly contrib- a1111111111 utes to a lack of mutant phenotypes. -
A Computational Approach for Defining a Signature of Β-Cell Golgi Stress in Diabetes Mellitus
Page 1 of 781 Diabetes A Computational Approach for Defining a Signature of β-Cell Golgi Stress in Diabetes Mellitus Robert N. Bone1,6,7, Olufunmilola Oyebamiji2, Sayali Talware2, Sharmila Selvaraj2, Preethi Krishnan3,6, Farooq Syed1,6,7, Huanmei Wu2, Carmella Evans-Molina 1,3,4,5,6,7,8* Departments of 1Pediatrics, 3Medicine, 4Anatomy, Cell Biology & Physiology, 5Biochemistry & Molecular Biology, the 6Center for Diabetes & Metabolic Diseases, and the 7Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202; 2Department of BioHealth Informatics, Indiana University-Purdue University Indianapolis, Indianapolis, IN, 46202; 8Roudebush VA Medical Center, Indianapolis, IN 46202. *Corresponding Author(s): Carmella Evans-Molina, MD, PhD ([email protected]) Indiana University School of Medicine, 635 Barnhill Drive, MS 2031A, Indianapolis, IN 46202, Telephone: (317) 274-4145, Fax (317) 274-4107 Running Title: Golgi Stress Response in Diabetes Word Count: 4358 Number of Figures: 6 Keywords: Golgi apparatus stress, Islets, β cell, Type 1 diabetes, Type 2 diabetes 1 Diabetes Publish Ahead of Print, published online August 20, 2020 Diabetes Page 2 of 781 ABSTRACT The Golgi apparatus (GA) is an important site of insulin processing and granule maturation, but whether GA organelle dysfunction and GA stress are present in the diabetic β-cell has not been tested. We utilized an informatics-based approach to develop a transcriptional signature of β-cell GA stress using existing RNA sequencing and microarray datasets generated using human islets from donors with diabetes and islets where type 1(T1D) and type 2 diabetes (T2D) had been modeled ex vivo. To narrow our results to GA-specific genes, we applied a filter set of 1,030 genes accepted as GA associated. -
PQBP1, a Factor Linked to Intellectual Disability, Affects Alternative Splicing Associated with Neurite Outgrowth
Downloaded from genesdev.cshlp.org on September 26, 2021 - Published by Cold Spring Harbor Laboratory Press PQBP1, a factor linked to intellectual disability, affects alternative splicing associated with neurite outgrowth Qingqing Wang,1 Michael J. Moore,2 Guillaume Adelmant,3,4,5 Jarrod A. Marto,3,4,5 and Pamela A. Silver1,6,7 1Department of Systems Biology, Harvard Medical School, Boston, Massachusetts 02115, USA; 2Laboratory of Molecular Neuro- Oncology, The Rockefeller University, New York, New York 10065, USA; 3Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts 02115, USA; 4Blais Proteomics Center, 5Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA; 6Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, Massachusetts 02115, USA Polyglutamine-binding protein 1 (PQBP1) is a highly conserved protein associated with neurodegenerative disorders. Here, we identify PQBP1 as an alternative messenger RNA (mRNA) splicing (AS) effector capable of influencing splicing of multiple mRNA targets. PQBP1 is associated with many splicing factors, including the key U2 small nuclear ribonucleoprotein (snRNP) component SF3B1 (subunit 1 of the splicing factor 3B [SF3B] protein complex). Loss of functional PQBP1 reduced SF3B1 substrate mRNA association and led to significant changes in AS patterns. Depletion of PQBP1 in primary mouse neurons reduced dendritic outgrowth and altered AS of mRNAs enriched for functions in neuron projection development. Disease-linked PQBP1 mutants were deficient in splicing factor associations and could not complement neurite outgrowth defects. Our results indicate that PQBP1 can affect the AS of multiple mRNAs and indicate specific affected targets whose splice site determination may contribute to the disease phenotype in PQBP1-linked neurological disorders. -
The Intellectual Disability Gene PQBP1 Rescues Alzheimer’S Disease
Molecular Psychiatry (2018) 23:2090–2110 https://doi.org/10.1038/s41380-018-0253-8 ARTICLE The intellectual disability gene PQBP1 rescues Alzheimer’s disease pathology 1 1 1 1 1 2 Hikari Tanaka ● Kanoh Kondo ● Xigui Chen ● Hidenori Homma ● Kazuhiko Tagawa ● Aurelian Kerever ● 2 3 3 4 1 1,5 Shigeki Aoki ● Takashi Saito ● Takaomi Saido ● Shin-ichi Muramatsu ● Kyota Fujita ● Hitoshi Okazawa Received: 9 May 2018 / Revised: 9 August 2018 / Accepted: 6 September 2018 / Published online: 3 October 2018 © The Author(s) 2018. This article is published with open access Abstract Early-phase pathologies of Alzheimer’s disease (AD) are attracting much attention after clinical trials of drugs designed to remove beta-amyloid (Aβ) aggregates failed to recover memory and cognitive function in symptomatic AD patients. Here, we show that phosphorylation of serine/arginine repetitive matrix 2 (SRRM2) at Ser1068, which is observed in the brains of early phase AD mouse models and postmortem end-stage AD patients, prevents its nuclear translocation by inhibiting interaction with T-complex protein subunit α. SRRM2 deficiency in neurons destabilized polyglutamine binding protein 1 (PQBP1), a causative gene for intellectual disability (ID), greatly affecting the splicing patterns of synapse-related genes, as 1234567890();,: 1234567890();,: demonstrated in a newly generated PQBP1-conditional knockout model. PQBP1 and SRRM2 were downregulated in cortical neurons of human AD patients and mouse AD models, and the AAV-PQBP1 vector recovered RNA splicing, the synapse phenotype, and the cognitive decline in the two mouse models. Finally, the kinases responsible for the phosphorylation of SRRM2 at Ser1068 were identified as ERK1/2 (MAPK3/1). -
Table of Contents
Table of Contents 1. - EXAMINING ATTITUDES AND WILLINGNESS TO PAY FOR AQUACULTURED SEAFOOD ATTRIBUTES I. Ko Britwum * II. Caroline Noblet 2. - Development of a Hybrid Thermoplastic Composite and Concrete Deck System I. Benjamin Smith * II. William Davids 3. - Undergraduate Nursing Students’ Perspectives and Attitudes Caring for Elderly Patients at End of Life I. Karen Chase * II. Patricia Poirier 4. - Backpack Programs: How Maine Elementary Schools Are Tackling Childhood Hunger I. Julianna Acheson * II. Julia Van Steenberge III. Dean Rando IV. Ashlee Atchinson V. Sandra Caron 5. - Using Structure from Motion and 3D Printing as a Method for Preserving the Petroglyphs of Machias Bay, Maine I. Kendra Bird * II. Lisa Neuman 6. - Capacity Assessment of Older T-Beam Bridges Using Field Load Testing and Nonlinear Proxy Finite-Element Analysis I. Andrew Schanck * II. William Davids 7. - Interventions Supporting Social Communication Skills in Preschool-Aged Children with Autism Spectrum Disorder I. Paige Hanson * II. Paige Castonguay III. Heather Lowry IV. Taylor Dupont V. Paige Lane 8. - Attitudes Towards Immigration Following the 2018 Family Separation Crisis: Content Analysis of Tweets in The Washington Post vs Fox News I. Rebecca Blodgett * II. Vincent Eze III. Ariana Cruwys IV. Sandra Caron 9. - Nurses Role in Central Line-Associated Bloodstream Infection Prevention I. Laura Roberts * II. Julia Schnee III. Bronwyn West IV. Alex Roderick V. Valerie Herbert 10. - Overwintering strategies of the salmon louse Lepeophtheirus salmonis I. Emma Taccardi * II. Carrie Byron III. Ian Bricknell 11. - The eects of diverse aged enrollment on community school literacy rates in rural Zambia: Case study on Impact Network International schools, Eastern Province Zambia I. -
Induced Early Expression of Mrf4 but Not Myog Rescues Myogenesis in the Myod/Myf5 Double- Morphant Zebrafish Embryo
Research Article 481 Induced early expression of mrf4 but not myog rescues myogenesis in the myod/myf5 double- morphant zebrafish embryo Esther Schnapp1,*, Anna Silvia Pistocchi2,*, Evangelia Karampetsou2, Efrem Foglia2, Carla Lora Lamia2, Franco Cotelli2,‡ and Giulio Cossu1,2,‡ 1Stem Cell Research Institute, DiBiT, San Raffaele Scientific Institute, 58 via Olgettina, 20132 Milan, Italy 2Department of Biology, University of Milan, 26 via Celoria, 20133 Milan, Italy *These authors contributed equally to this work ‡Authors for correspondence (e-mails: [email protected]; [email protected]) Accepted 13 October 2008 Journal of Cell Science 122, 481-488 Published by The Company of Biologists 2009 doi:10.1242/jcs.038356 Summary Muscle regulatory factors activate myogenesis in all vertebrates, inhibition, we were able to investigate how myogenesis occurs in but their role has been studied in great detail only in the mouse the absence of a myotome. We report that in the complete absence embryo, where all but myogenin – Myod, Myf5 and Mrf4 – are of a myotome, subsequent myogenesis is abolished, whereas sufficient to activate (albeit not completely) skeletal myogenesis. myogenesis does proceed, albeit abnormally, when the In the zebrafish embryo, myod and myf5 are required for morpholino inhibition was not complete. Therefore our data also induction of myogenesis because their simultaneous ablation show that the early myotome is essential for subsequent skeletal prevents muscle development. Here we show that mrf4 but not muscle differentiation and patterning in the zebrafish. myog can fully rescue myogenesis in the myod/myf5 double morphant via a selective and robust activation of myod, in keeping Supplementary material available online at with its chromatin-remodelling function in vitro. -
Characterization of Ncf1 Mutants in a Zebrafish Model of Innate Immune Function with Human Influenza a Virus Infection
The University of Maine DigitalCommons@UMaine Honors College Spring 5-2020 Characterization of ncf1 Mutants in a Zebrafish Model of Innate Immune Function with Human Influenza A Virus Infection Lily Charpentier Follow this and additional works at: https://digitalcommons.library.umaine.edu/honors Part of the Immunology and Infectious Disease Commons, Influenza Humans Commons, and the Virus Diseases Commons This Honors Thesis is brought to you for free and open access by DigitalCommons@UMaine. It has been accepted for inclusion in Honors College by an authorized administrator of DigitalCommons@UMaine. For more information, please contact [email protected]. CHARACTERIZATION OF NCF1 MUTANTS IN A ZEBRAFISH MODEL OF INNATE IMMUNE FUNCTION WITH HUMAN INFLUENZA A VIRUS INFECTION by Lily Charpentier A Thesis Submitted to Partial Fulfillment of the Requirements for a Degree with Honors (Biochemistry) The Honors College The University of Maine May 2020 Advisory Committee: Benjamin L. King, Assistant Professor of Bioinformatics, Advisor Edward Bernard, Lecturer & Undergraduate Coordinator of Molecular & Biomedical Sciences R.W. Estela, Honors Preceptor Sally D. Molloy, Assistant Professor of Genomics Robert Wheeler, Associate Professor of Microbiology ABSTRACT Seasonal influenza A virus (IAV) infections and their associated respiratory diseases are the cause of an estimated 650,000 deaths each year, according to the World Health Organization. The zebrafish (Danio rerio) is a powerful vertebrate model to study innate immune function and host-pathogen interactions as the function of neutrophils and other phagocytes can be characterized in vivo. Preliminary studies have shown an increase in neutrophil respiratory burst activity to eliminate the invading pathogen, yet little is known of all of the mechanisms involved in neutrophil function. -
Specificity Profiles of Protein Recognition Domains in the Molecular Medicine
Aus dem Institut für Medizinische Immunologie der Medizinischen Fakultät Charité – Universitätsmedizin Berlin DISSERTATION Specificity Profiles of Protein Recognition Domains in the Molecular Medicine zur Erlangung des akademischen Grades Doctor rerum medicinalium (Dr. rer. medic.) vorgelegt der Medizinischen Fakultät Charité – Universitätsmedizin Berlin von Víctor E. Tapia Mancilla aus Valparaíso, Chile Datum der Promotion: .. 22.06.2014.......................... Inhaltsverzeichnis Zusammenfassung.................................................................................................................................................1 ABSTRAKT......................................................................................................................................................................1 ABSTRACT ....................................................................................................................................................................2 INTRODUCTION ............................................................................................................................................................3 Specificity Profiles......................................................................................................................................................3 BAG-Family Co-Chaperone Commitment in Proteostasis.........................................................................................4 The Intriguing Role of PQBP1 in X-LID.....................................................................................................................5 -
HHS Public Access Author Manuscript
HHS Public Access Author manuscript Author Manuscript Author ManuscriptNat Genet Author Manuscript. Author manuscript; Author Manuscript available in PMC 2015 November 01. Published in final edited form as: Nat Genet. 2015 May ; 47(5): 528–534. doi:10.1038/ng.3256. Biallelic mutations in SNX14 cause a syndromic form of cerebellar atrophy and lysosome-autophagosome dysfunction Naiara Akizu1,2,3, Vincent Cantagrel4, Maha S. Zaki5, Lihadh Al-Gazali6, Xin Wang1,2, Rasim Ozgur Rosti1,2, Esra Dikoglu1,2, Antoinette Bernabe Gelot7,8, Basak Rosti1,2, Keith K. Vaux1,2, Eric M. Scott1,2, Jennifer L. Silhavy1,2, Jana Schroth1,2, Brett Copeland1,2, Ashleigh E. Schaffer1,2, Philip Gordts9, Jeffrey D. Esko9, Matthew D. Buschman10, Seth J. Fields10, Gennaro Napolitano11, R. Koksal Ozgul12, Mahmut Samil Sagiroglu13, Matloob Azam14, Samira Ismail5, Mona Aglan5, Laila Selim15, Iman Gamal15, Sawsan Abdel Hadi15, Amera El Badawy15, Abdelrahim A. Sadek16, Faezeh Mojahedi17, Hulya Kayserili18, Amira Masri19, Laila Bastaki20, Samia Temtamy5, Ulrich Müller3, Isabelle Desguerre21, Jean- Laurent Casanova2,22,23, Ali Dursun24, Murat Gunel25,26,27, Stacey B. Gabriel28, Pascale de Lonlay29, and Joseph G. Gleeson1,2,30 1Laboratory for Pediatric Brain Disease, The Rockefeller University, New York, NY 10065. USA. 2Howard Hughes Medical Institute. Chevy Chase, Maryland, USA. 3Dorris Neuroscience Center, Scripps Research Institute, La Jolla, CA 92093, USA. 4Institut Imagine, INSERM U1163, Hôpital Necker Enfants Malades, PARIS, France 75743. 5Clinical Genetics Department, Human Genetics and Genome Research Division, National Research Centre, Cairo, 12311 Egypt. 6College of Medicine and Health Sciences, UAE University, United Arab Emirates. 7AP-HP, Hôpital Armand Trousseau, Laboratoire d’Anatomie Pathologique, Neuropathologie, Paris, France. -
BMC Developmental Biology Biomed Central
CORE Metadata, citation and similar papers at core.ac.uk Provided by PubMed Central BMC Developmental Biology BioMed Central Research article Open Access laminin alpha 1 gene is essential for normal lens development in zebrafish Natalya S Zinkevich†1,2, Dmitry V Bosenko†1,2, Brian A Link2 and Elena V Semina*1,2,3 Address: 1Department of Pediatrics, Medical College of Wisconsin, Milwaukee, WI 53226, USA, 2Departments of Cell Biology, Neurobiology and Anatomy, Medical College of Wisconsin, Milwaukee, WI 53226, USA and 3Departments of Human and Molecular Genetics Center, Medical College of Wisconsin, Milwaukee, WI 53226, USA Email: Natalya S Zinkevich - [email protected]; Dmitry V Bosenko - [email protected]; Brian A Link - [email protected]; Elena V Semina* - [email protected] * Corresponding author †Equal contributors Published: 07 March 2006 Received: 28 September 2005 Accepted: 07 March 2006 BMC Developmental Biology2006, 6:13 doi:10.1186/1471-213X-6-13 This article is available from: http://www.biomedcentral.com/1471-213X/6/13 © 2006Zinkevich et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Abstract Background: Laminins represent major components of basement membranes and play various roles in embryonic and adult tissues. The functional laminin molecule consists of three chains, alpha, beta and gamma, encoded by separate genes. There are twelve different laminin genes identified in mammals to date that are highly homologous in their sequence but different in their tissue distribution. -
Mutations in the Polyglutamine Binding Protein 1 Gene Cause X
BRIEF COMMUNICATIONS 1. Schrimshaw, N.S. & Murray, E.B. Am. J. Clin. Nutr. 48, 1059–1179 (1988). 9. Dunner, S. et al. Genet. Sel. Evol. 35, 103–118 (2003). 2. Feldman, M.W. & Cavalli-Sforza, L.L. in Mathematical evolutionary theory (ed. 10. Loftus, R.T. et al. Mol. Ecol. 8, 2015–2022 (1999). Feldman, M.W.) 145–173 (Princeton University Press, Princeton, New Jersey, 11. MacHugh, D.E., Loftus, R.T., Cunningham, P. & Bradley, D.G. Anim. Genet. 29, 1989). 333–340 (1998). 3. Midgley, M.S. TRB Culture: The First Farmers of the North European Plain 12. Medjugorac, I., Kustermann, W., Lazar, P., Russ, I. & Pirchner, F. Anim. Genet. 25, (Edinburgh University Press, Edinburgh, 1992). 19–27 (1994). 4. Enattah, N.S. et al. Nat. Genet. 30, 233–237 (2002). 13. Troy, C. et al. Nature 410, 1088–1091 (2001). 5. Ward, R., Honeycutt, L. & Derr, J.N. Genetics 147, 1863–1872 (1997). 14. Hill, A.V., Jepson, A., Plebanski, M. & Gilbert, S.C. Philos. Trans. R. Soc. Lond. B 6. Dudd, S. & Evershed, P. Science 282, 1478–1480 (1998). Biol. Sci. 352, 1317–1325 (1997). 7. Balasse, M. & Tresset, A. J. Archaeol. Sci. 29, 853–859 (2002). 15. Zvelebil, M. in Archaeogenetics: DNA and the Population History of Europe (ed. 8. Tishkoff, S.A. et al. Science 293, 455–462 (2001). Boyle, K.) 57–79 (MacDonald Institute Cambridge, Cambridge, 2000). Mutations in the polyglutamine deleted in affected males of family N40 (ref. 4). In all families, these mutations segregated with the disease and were present in all oblig- binding protein 1 gene cause X- ate heterozygotes that we tested. -
NIH Public Access Author Manuscript Nature
NIH Public Access Author Manuscript Nature. Author manuscript; available in PMC 2013 November 08. NIH-PA Author ManuscriptPublished NIH-PA Author Manuscript in final edited NIH-PA Author Manuscript form as: Nature. 2009 January 8; 457(7226): . doi:10.1038/nature07520. The dynein regulatory complex is required for ciliary motility and otolith biogenesis in the inner ear Jessica R. Colantonio1,*, Julien Vermot4,*, David Wu4, Adam D. Langenbacher2, Scott Fraser4, Jau-Nian Chen2,3, and Kent L. Hill1,3 1Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, California 90095, USA 2Department of Molecular, Cell, and Developmental Biology, University of California, Los Angeles, California 90095, USA 3Molecular Biology Institute, University of California, Los Angeles, California 90095, USA 4Biological Imaging Center, Beckman Institute, California Institute of Technology, Pasadena, California 91125, USA Abstract In teleosts, proper balance and hearing depend on mechanical sensors in the inner ear. These sensors include actin-based microvilli and microtubule-based cilia that extend from the surface of sensory hair cells and attach to biomineralized ‘ear stones’ (or otoliths)1. Otolith number, size and placement are under strict developmental control, but the mechanisms that ensure otolith assembly atop specific cells of the sensory epithelium are unclear. Here we demonstrate that cilia motility is required for normal otolith assembly and localization. Using in vivo video microscopy, we show that motile tether cilia at opposite poles of the otic vesicle create fluid vortices that attract otolith precursor particles, thereby biasing an otherwise random distribution to direct localized otolith seeding on tether cilia. Independent knockdown of subunits for the dynein regulatory complex and outer-arm dynein disrupt cilia motility, leading to defective otolith biogenesis.