DOCSLIB.ORG

Dissecting Mechanisms Controlling Neural Network Formation in Drosophila Melanogaster

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Dissecting Mechanisms Controlling Neural Network Formation in Drosophila Melanogaster Dissecting mechanisms controlling neural network formation in Drosophila melanogaster Hong Long Department of Neurology and Neurosurgery McGill University Montreal, Quebec, Canada August 2009 A thesis submitted to the Faculty of Graduate Studies and Research in partial fulfillment of the requirements for the Ph.D. degree in Neuroscience © Hong Long, 2009 1 Library and Archives Bibliothèque et Canada Archives Canada Published Heritage Direction du Branch Patrimoine de l’édition 395 Wellington Street 395, rue Wellington Ottawa ON K1A 0N4 Ottawa ON K1A 0N4 Canada Canada Your file Votre référence ISBN: 978-0-494-66458-2 Our file Notre référence ISBN: 978-0-494-66458-2 NOTICE: AVIS: The author has granted a non- L’auteur a accordé une licence non exclusive exclusive license allowing Library and permettant à la Bibliothèque et Archives Archives Canada to reproduce, Canada de reproduire, publier, archiver, publish, archive, preserve, conserve, sauvegarder, conserver, transmettre au public communicate to the public by par télécommunication ou par l’Internet, prêter, telecommunication or on the Internet, distribuer et vendre des thèses partout dans le loan, distribute and sell theses monde, à des fins commerciales ou autres, sur worldwide, for commercial or non- support microforme, papier, électronique et/ou commercial purposes, in microform, autres formats. paper, electronic and/or any other formats. The author retains copyright L’auteur conserve la propriété du droit d’auteur ownership and moral rights in this et des droits moraux qui protège cette thèse. Ni thesis. Neither the thesis nor la thèse ni des extraits substantiels de celle-ci substantial extracts from it may be ne doivent être imprimés ou autrement printed or otherwise reproduced reproduits sans son autorisation. without the author’s permission. In compliance with the Canadian Conformément à la loi canadienne sur la Privacy Act some supporting forms protection de la vie privée, quelques may have been removed from this formulaires secondaires ont été enlevés de thesis. cette thèse. While these forms may be included Bien que ces formulaires aient inclus dans in the document page count, their la pagination, il n’y aura aucun contenu removal does not represent any loss manquant. of content from the thesis. Table of contents List of figures and tables 8 List of abbreviations used 10 Abstract 21 Résumé 23 Acknowledgements 25 Contribution of co-authors 26 Original contributions to knowledge 27 Chapter 1. Introduction 28 1.1 Axonal guidance, targeting, and tiling 28 1.1.1 Growth cone 28 1.1.2 Guidepost cell, Pioneer axon, and the labelled pathway 29 1.1.3 Layer-specific targeting 31 1.1.4 Topographic Mapping 32 1.1.5 Axon tiling and self-avoidance 33 1.1.6 Drosophila visual system 35 1.1.7 Review of molecules and signalling pathways involved in R-cell axon guidance, targeting, and tiling. 39 1.1.7.1 Nuclear proteins 39 1.1.7.1.1 Brakeless 39 2 1.1.7.1.2 Runt 41 1.1.7.1.3 Nuclear factors YC 42 1.1.7.1.4 Sequoia 44 1.1.7.2 Cytoplasmic signalling proteins 46 1.1.7.2.1 Dreadlocks 46 1.1.7.2.2 Misshapen 47 1.1.7.2.3 Bifocal 49 1.1.7.2.4 p21-activated kinase 51 1.1.7.2.5 Trio 53 1.1.7.2.6 Rho-GTPase Rac 57 1.1.7.3 Cell surface proteins and secreted proteins 58 1.1.7.3.1 Insulin Receptor 58 1.1.7.3.2 N-Cadherin 60 1.1.7.3.3 Flamingo 68 1.1.7.3.4 Leukocyte common antigen-related RPTP 71 1.1.7.3.5 PTP69D 74 1.1.7.3.6 Capricious 76 1.1.7.3.7 Golden Goal 78 1.1.7.3.8 Anaplastic lymphoma kinase and Jelly Belly 80 1.1.7.3.9 Off-track and Semaphorin-1a 84 1.1.7.3.10 Dfrizzled2 and DWnt4 87 1.1.7.3.11 Transforming Growth Factor β /Activin 89 1.1.8 Review of genes involved in glia and target field development 91 3 1.1.8.1 Genes involved in glia development, migration, and function 91 1.1.8.1.1 Decapentaplegic, Hedgehog, and Gilgamesh 91 1.1.8.1.2 Wingless, Dpp, and Glial cell missing 93 1.1.8.1.3 Non-stop, SAGA complex and Histone H2B 94 1.1.8.1.4 JAB1/CSN5 95 1.1.8.2 Genes involved in the lamina-lobula boundary formation 96 1.1.8.2.1 Robo and Slit 96 1.1.8.2.2 Egghead 98 1.1.8.3 Genes involved in target neuron development 99 1.2 Dendrite patterning and function 101 1.2.1 Dendrite development, arborisation, and patterning 101 1.2.1.1 Dendrite outgrowth 102 1.2.1.2 Dendrite guidance and targeting 104 1.2.1.3 Dendrite branching and spine formation 106 1.2.1.4 Dendrite heteroneuronal tiling 108 1.2.1.5 Dendrite isoneuronal self-avoidance 110 1.2.1.6 Dendrite maintenance 112 1.2.1.7 Dendrite remodelling 115 1.2.2 Drosophila PNS dendritic arborisation (da) neurons 117 1.3 An overview of my studies and their contributions to our knowledge of the 121 related fields 1.3.1 My work in axon guidance and tiling in the fly visual system 121 1.3.2 My analyses in dendritic patterning in the fly da neurons 124 4 Chapter 2. De Novo GMP Synthesis Is Required for Axon Guidance in Drosophila 126 Summary 128 Introduction 129 Materials and methods 132 Genetics 132 Molecular Biology 132 Histology and Immunohistochemistry 133 Results 134 Figures 144 Table 160 Discussion 161 Acknowledgements 165 References 166 Chapter 3. Dendrite branching and self-avoidance are controlled by Turtle, a conserved IgSF protein in Drosophila 171 Summary 173 Introduction 174 Materials and methods 177 Fly stocks and genetics 177 Imaging and quantification 178 Immunohistochemistry 178 5 Results 180 Figures 189 Table 213 Discussion 214 Acknowledgements 221 References 222 Chapter 4. Characterizing gene Dnrk in Drosophila 227 Summary 229 Introduction 231 Materials and methods 243 Genetics 243 Molecular biology 243 Histology and Immunohistochemistry 244 Results 246 Figures 259 Table 278 Discussion 279 Acknowledgements 282 References 283 Chapter 5. General discussion 296 5.1 The involvement of de novo GMP synthesis in R-cell axon guidance 298 6 5.1.1 de novo GMP synthesis versus the salvage synthesis pathway 298 5.1.2 How GMP level is controlled within the cell? 299 5.1.3 Signaling events of GMP 301 5.1.4 bur also functions in motor axon guidance 302 5.1.5 Defasciculation, a requirement for layer-specific R1-R6 targeting? 303 5.1.6 Is the de novo GMP synthesis required for neural network formation in mammals? 304 5.2 The function of Turtle in dendrite branching and patterning 304 5.2.1 Domain requirement and the possible homotypic function of Tutl 304 5.2.2 The dendrite patterning phenotype in class I neuron 306 5.2.3 Functional relationship between tutl and other known genes in dendrite development 307 5.2.4 Potential role of tutl in the VNC? 307 5.2.5 Tutl functions in R7 axon tiling in the fly visual system 308 5.2.6 The function of Tutl in fly behavior 308 5.2.7 The function of the mammalian homolog of Tutl 309 5.3 The function of Dnrk in fly 310 5.3.1 The potential redundancy between Dnrk and Dror 310 5.3.2 The potential function of Dnrk in the VNC 311 5.3.3 Genetic interaction between Dnrk and DWnt5 312 References 314 7 List of figures and tables Chapter 2, figure 1: Molecular characterization of the bur gene 144 Chapter 2, figure 2: Mutations in the bur gene disrupted R-cell axon pathfinding 146 Chapter 2, figure 3: bur is not required for lamina-specific termination of R2-R5… 148 Chapter 2, figure 4: R-cell differentiation and patterning remained normal in bur… 150 Chapter 2, figure 5: Rescue of the R-cell pathfinding phenotype by expressing… 152 Chapter 2, figure 6: Mutations in the ras gene caused a bur-like phenotype in R… 154 Chapter 2, figure 7: Depleting guanine from the fly food did not affect R-cell axon 156 Chapter 2, figure 8: Reducing the dosage of bur enhanced the Rac phenotype 158 Chapter 2, table 1: Transgenic rescue of R-cell axonal hyperfasciculation… 160 Chapter 3, figure 1: Tutl protein structure, tutl alleles, and Tutl expression in da… 189 Chapter 3, figure 2: tutl is required to restrain dendrite branching in class I da… 191 Chapter 3, figure 3: Class II and class III DA neurons are unaffected in tutl23… 193 Chapter 3, figure 4: tutl is required for dendrite self-avoidance in class IV da… 195 Chapter 3, figure 5: tutl mutants exhibit normal dendritic tiling among class IV… 197 Chapter 3, figure 6: Overexpression of Tutl inhibits dendrite branching in class… 199 Chapter 3, figure 7: The cytoplasmic tail of Tutl is dispensable for function in… 201 Chapter 3, figure S1: Additional examples of dendrite branching and self-… 203 Chapter 3, figure S2: Quantification of the effects of tutl mutations on additional… 205 Chapter 3, figure S3: Overexpression of Tutl is not sufficient to induce dendrite… 207 Chapter 3, figure S4: Tutl expression in mutants of ab, ss, kn, and cut 209 8 Chapter 3, figure S5: Expression of Tutl and TutlΔcyto in class I da neurons of tutl… 211 Chapter 3, table S1: Genetic Interaction Experiments for tutl and trc 213 Chapter 4, figure 1: Predicted domain structure of Ror family proteins 259 Chapter 4, figure 2: Molecular characterization of the Dnrk gene 261 Chapter 4, figure 3: Mutation in the Dnrk gene disrupted R-cell axon guidance… 263 Chapter 4, figure 4: The adult R-cell axon projection pattern in Dnrk mutant was… 266 Chapter 4, figure 5: Dnrk mutant did not display axon guidance defect in the VNC… 268 Chapter 4, figure 6: Dendrite development and tiling pattern in wild type and… 270 Chapter 4, figure 7: Potential functional redundancy between Dnrk and Dror in… 272 Chapter 4, figure 8: Overexpression of UASDnrk in the eye and in the da… 274 Chapter 4, figure 9: The overexpression of UASDnrk in the wing could change… 276 Chapter 4, table 1: Modifier screen on the loss-of-cross-vein phenotype
Load more

Recommended publications
  • Neuregulin-1 Potentiates Agrin-Induced Acetylcholine Receptor Clustering Through Muscle-Specific Kinase Phosphorylation
    Research Article 1531 Neuregulin-1 potentiates agrin-induced acetylcholine receptor clustering through muscle-specific kinase phosphorylation Shyuan T. Ngo1, Rebecca N. Cole3, Nana Sunn2, William D. Phillips3,* and Peter G. Noakes1,2,*,` 1School of Biomedical Sciences, University of Queensland, St. Lucia, 4072, Queensland, Australia 2Queensland Brain Institute, University of Queensland, St. Lucia, 4072, Queensland, Australia 3Physiology and Bosch Institute, The University of Sydney, New South Wales, 2006, Australia *These authors contributed equally to this work `Author for correspondence ([email protected]) Accepted 14 November 2011 Journal of Cell Science 125, 1531–1543 ß 2012. Published by The Company of Biologists Ltd doi: 10.1242/jcs.095109 Summary At neuromuscular synapses, neural agrin (n-agrin) stabilizes embryonic postsynaptic acetylcholine receptor (AChR) clusters by signalling through the muscle-specific kinase (MuSK) complex. Live imaging of cultured myotubes showed that the formation and disassembly of primitive AChR clusters is a dynamic and reversible process favoured by n-agrin, and possibly other synaptic signals. Neuregulin-1 is a growth factor that can act through muscle ErbB receptor kinases to enhance synaptic gene transcription. Recent studies suggest that neuregulin-1–ErbB signalling can modulate n-agrin-induced AChR clustering independently of its effects on transcription. Here we report that neuregulin-1 increased the size of developing AChR clusters when injected into muscles of embryonic mice. We investigated this phenomenon using cultured myotubes, and found that in the ongoing presence of n-agrin, neuregulin-1 potentiates AChR clustering by increasing the tyrosine phosphorylation of MuSK. This potentiation could be blocked by inhibiting Shp2, a postsynaptic tyrosine phosphatase known to modulate the activity of MuSK.
    [Show full text]
  • Induction of Myasthenia by Immunization Against Muscle- Specific Kinase
    Induction of myasthenia by immunization against muscle- specific kinase Kazuhiro Shigemoto, … , Norifumi Ueda,, Seiji Matsuda J Clin Invest. 2006;116(4):1016-1024. https://doi.org/10.1172/JCI21545. Research Article Autoimmunity Muscle-specific kinase (MuSK) is critical for the synaptic clustering of nicotinic acetylcholine receptors (AChRs) and plays multiple roles in the organization and maintenance of neuromuscular junctions (NMJs). MuSK is activated by agrin, which is released from motoneurons, and induces AChR clustering at the postsynaptic membrane. Although autoantibodies against the ectodomain of MuSK have been found in a proportion of patients with generalized myasthenia gravis (MG), it is unclear whether MuSK autoantibodies are the causative agent of generalized MG. In the present study, rabbits immunized with MuSK ectodomain protein manifested MG-like muscle weakness with a reduction of AChR clustering at the NMJs. The autoantibodies activated MuSK and blocked AChR clustering induced by agrin or by mediators that do not activate MuSK. Thus MuSK autoantibodies rigorously inhibit AChR clustering mediated by multiple pathways, an outcome that broadens our general comprehension of the pathogenesis of MG. Find the latest version: https://jci.me/21545/pdf Research article Induction of myasthenia by immunization against muscle-specific kinase Kazuhiro Shigemoto,1,2 Sachiho Kubo,2 Naoki Maruyama,2 Naohito Hato,3 Hiroyuki Yamada,3 Chen Jie,4 Naoto Kobayashi,4 Katsumi Mominoki,5 Yasuhito Abe,6 Norifumi Ueda,6 and Seiji Matsuda4 1Department of Preventive Medicine, Ehime University School of Medicine, Ehime, Japan. 2Department of Molecular Pathology, Tokyo Metropolitan Institute for Gerontology, Tokyo, Japan. 3Department of Otolaryngology and 4Department of Integrated Basic Medical Science, Ehime University School of Medicine, Ehime, Japan.
    [Show full text]
  • Download the Abstract Book
    1 Exploring the male-induced female reproduction of Schistosoma mansoni in a novel medium Jipeng Wang1, Rui Chen1, James Collins1 1) UT Southwestern Medical Center. Schistosomiasis is a neglected tropical disease caused by schistosome parasites that infect over 200 million people. The prodigious egg output of these parasites is the sole driver of pathology due to infection. Female schistosomes rely on continuous pairing with male worms to fuel the maturation of their reproductive organs, yet our understanding of their sexual reproduction is limited because egg production is not sustained for more than a few days in vitro. Here, we explore the process of male-stimulated female maturation in our newly developed ABC169 medium and demonstrate that physical contact with a male worm, and not insemination, is sufficient to induce female development and the production of viable parthenogenetic haploid embryos. By performing an RNAi screen for genes whose expression was enriched in the female reproductive organs, we identify a single nuclear hormone receptor that is required for differentiation and maturation of germ line stem cells in female gonad. Furthermore, we screen genes in non-reproductive tissues that maybe involved in mediating cell signaling during the male-female interplay and identify a transcription factor gli1 whose knockdown prevents male worms from inducing the female sexual maturation while having no effect on male:female pairing. Using RNA-seq, we characterize the gene expression changes of male worms after gli1 knockdown as well as the female transcriptomic changes after pairing with gli1-knockdown males. We are currently exploring the downstream genes of this transcription factor that may mediate the male stimulus associated with pairing.
    [Show full text]
  • (12) United States Patent (10) Patent N0.: US 7,267,820 B2 Vincent Et A]
    US007267820B2 (12) United States Patent (10) Patent N0.: US 7,267,820 B2 Vincent et a]. (45) Date of Patent: Sep. 11,2007 (54) NEUROTRANSMISSION DISORDERS Glass, D]. et a1. Agrin acts via a MuSK receptor complex. Cell. May 17, 1996;85(4):513-23. (75) Inventors: Angela Vincent, Oxford (GB); Werner Hoch W, et al., Auto-antibodies to the receptor tyrosine kinase Hoch, Houston, TX (US) MuSK in patients with myasthenia gravis without acetycholine receptor antibodies. Nat Med. Mar. 2001;7(3):365-8. (73) Assignees: Isis Innovation Limited, Oxford (GB); Hoch, W., et a1. Structural domains of agrin required for clustering of nicotinic acetylcholine receptors. EMBO J. Jun. 15, Max-Planck Gesellschaft zur 1994;13(12):2814-21. Foerderung der Wissenschaften e.V., Hopf. C., Hoch, W. Heparin inhibits acetycholine receptor-aggre Munich (DE) gation at two distinct steps in the agrin-induced pathway. Eur J Neurosci. Jun. 1997;9(6):1170-7. ( * ) Notice: Subject to any disclaimer, the term of this Hopf, C., Hoch, W. DimeriZation of the muscle-speci?c kinase patent is extended or adjusted under 35 induces tyrosine phosphorylation of acetycholine receptors and their U.S.C. 154(b) by 506 days. aggregation on the surface of myotubes. J Biol Chem. Mar. 13, 1998;273(11):6467-73. (21) Appl. No.: 10/311,575 Hopf, C., Hoch, W. Tyrosine phosphorylation of the muscle-speci?c kinase is exclusively induced by acetycholine receptor-aggregating (22) PCT Filed: Jun. 15, 2001 agrin fragments. Eur JBiochem. Apr. 15, 1998;253(2):382-9. Lindstrom, J ., Seybold,.M.E., Lennon, V.A., Whittingham, S., (86) PCT N0.: PCT/GB01/02661 Duane, D.D., Antibody to acetycholine receptor in myasthenia gravis.
    [Show full text]
  • Proquest Dissertations
    L-type calcium channels mediate nicotinic acetylcholine receptor aggregation on cultured myotubes Item Type text; Dissertation-Reproduction (electronic) Authors Milholland, Rebecca Publisher The University of Arizona. Rights Copyright © is held by the author. Digital access to this material is made possible by the University Libraries, University of Arizona. Further transmission, reproduction or presentation (such as public display or performance) of protected items is prohibited except with permission of the author. Download date 06/10/2021 03:16:03 Link to Item http://hdl.handle.net/10150/280370 L-TYPE CALCIUM CHANNELS MEDIATE NICOTINIC ACETYLCHOLINE RECEPTOR AGGREGATION ON CULTURED MYOTUBES by Rebecca B. R. Milholland Copyright © Rebecca B. R. Milholland 2 0 0 3 A Dissertation Subnnitted to the Faculty of the GRADUATE INTERDISCIPLINARY PROGRAM IN PHARMACOLOGY AND TOXICOLOGY In Partial Fulfillment of the Requirements For the Degree of DOCTOR OF PHILOSOPHY In the Graduate college THE UNIVERSITY OF ARIZONA 2003 UMI Number: 3107021 Copyright 2003 by IVIilholland, Rebecca Bliss Ryan All rights reserved. UMI UMI Microform 3107021 Copyright 2004 by ProQuest Information and Learning Company. All rights reserved. This microform edition is protected against unauthorized copying under Title 17, United States Code. ProQuest Information and Learning Company 300 North Zeeb Road P.O. Box 1346 Ann Arbor, Ml 48106-1346 •7 THE UNIVERSITY OF ARIZONA ® GRADUATE COLLEGE As members of the Final Examination Committee, we certify that we have read the dissertation prepared by Rebecca B. R. Milholland entitled L-Type Calcium Channels Mediate AChR Aggregation on Cultured Myotubes and recommend that it be accepted as fulfilling the dissertation requirement for the Degree of Doctor of Philosophy /nai/18 ndrea Date Herman Gordon Date Pk Jj-- yL^ aul St.John ~ 7 Daa tie I I Daniel Stamer Date tCpJ Ro kas Date Final approval and acceptance of this dissertation is contingent upon the candidate's submission of the final copy of the dissertation to the Graduate College.
    [Show full text]
  • 13Th YSA Phd Symposium 2017 Book of Abstracts: Poster Presentations
    13th YSA PhD Symposium 2017 Book of Abstracts: Poster Presentations P 1 Efficient Subject Independent BCI based on Local Temporal Correlation Common Spatial Pattern method Hatamikia, S. (1)*, Nasrabadi, AM. (2) 1-university of Islamic Azad, Science and Research branch, Tehran, Iran,2-Center for Biomedical Engineering and Physics, Medical University Vienna, Austria, university of Shahed University Tehran, Iran [email protected] One of the main weaknesses of the proposed EEG-based Brain Computer interfaces (BCIs) is the requirement for specific subject training data to train a classifier. Almost all proposed BCIs in literature are custom-designed and dedicated to just one particular subject. Eliminating the calibration phase can be regarded as a good solution to enable new users to have an immediate interaction with BCIs. In addition, eliminating calibration training sessions has a vital role for those patients who have visual and audible deficiencies. Such patients do not have the mental or physical ability to perform training sessions needed for the subject dependent BCIs implementation. This study presents an efficient subject-independent approach for BCIs based on EEG signals. The main goal of this study is to develop ready-to-use motor imagery tasks based BCIs using other subjects' data, which can be utilizable for anyone, who is shown the system for the first time. To achieve this approach, we proposed a subject-independent method based on Local Temporal Correlation Common Spatial Pattern (LTCCSP) algorithm for feature selection and Genetic algorithm (GA) strategy, using Frobenious distance index, to have a simultaneous optimization of time interval and frequency. In this study, publicly available dataset IVa of the BCI competition III is used.
    [Show full text]
  • Muscle-Specific Receptor Tyrosine Kinase Endocytosis in Acetylcholine Receptor Clustering in Response to Agrin
    1688 • The Journal of Neuroscience, February 13, 2008 • 28(7):1688–1696 Cellular/Molecular Muscle-Specific Receptor Tyrosine Kinase Endocytosis in Acetylcholine Receptor Clustering in Response to Agrin Dan Zhu,1 Zhihua Yang,1 Zhenge Luo,2 Shiwen Luo,1 Wen C. Xiong,1 and Lin Mei1 1Program of Developmental Neurobiology, Institute of Molecular Medicine and Genetics, Medical College of Georgia, Augusta, Georgia 30912, and 2Institute of Neuroscience and Key Laboratory of Neurobiology, Shanghai Institutes for Biological Scineces, Chinese Academy of Sciences, Shanghai 200031, China Agrin, a factor used by motoneurons to direct acetylcholine receptor (AChR) clustering at the neuromuscular junction, initiates signal transduction by activating the muscle-specific receptor tyrosine kinase (MuSK). However, the underlying mechanisms remain poorly defined. Here, we demonstrated that MuSK became rapidly internalized in response to agrin, which appeared to be required for induced AChR clustering. Moreover, we provided evidence for a role of N-ethylmaleimide sensitive factor (NSF) in regulating MuSK endocytosis and subsequent signaling in response to agrin stimulation. NSF interacts directly with MuSK with nanomolar affinity, and treatment of muscle cells with the NSF inhibitor N-ethylmaleimide, mutation of NSF, or suppression of NSF expression all inhibited agrin-induced AChR clustering. Furthermore, suppression of NSF expression and NSF mutation attenuate MuSK downstream signaling. Our study reveals a potentially novel mechanism that regulates agrin/MuSK signaling cascade. Key words: neuromuscular junction; nicotinic acetylcholine receptors; agrin; endocytosis; MuSK; NSF Introduction dependent manner (Okada et al., 2006; Jones et al., 2007). Agrin/ The vertebrate neuromuscular junction (NMJ) is a synapse MuSK signaling is mediated or regulated by several interacting formed between motoneurons and skeletal muscle fibers.
    [Show full text]
  • (12) United States Patent (10) Patent No.: US 8,034,913 B2 Hunt Et Al
    USOO8034913B2 (12) United States Patent (10) Patent No.: US 8,034,913 B2 Hunt et al. (45) Date of Patent: Oct. 11, 2011 (54) RECOMBINANTLY MODIFIED PLASMIN FOREIGN PATENT DOCUMENTS CA 2045869 12/1991 (75) Inventors: Jennifer A. Hunt, Raleigh, NC (US); WO WO 97.27331 A2 7/1997 Valery Novokhatny, Raleigh, NC (US) WO WO99,05322 A1 2/1999 WO WOO1,9436.6 A1 12/2001 WO WOO2,5O290 A1 6, 2002 (73) Assignee: Grifols Therapeutics Inc., Research WO WOO3/O54232 A2 7, 2003 Triangle Park, NC (US) WO WO 2004/052228 A2 6, 2004 WO WO 2005,105990 11, 2005 WO WO 2007/047874 4/2007 (*) Notice: Subject to any disclaimer, the term of this WO WO 2009,0734.71 6, 2009 patent is extended or adjusted under 35 OTHER PUBLICATIONS U.S.C. 154(b) by 854 days. Hunt et al. Simplified recombinant plasmin: Production and func tional comparison of a novel thrombolytic molecule with plasma (21) Appl. No.: 11/568,023 derived plasmin. Thromb. Haemost 100:413-419, 2008.* Andrianov, S.I., et al., “Peculiarities of Hydrolytic Action of Plasmin, (22) PCT Filed: Apr. 21, 2005 Miniplasmin, Microplasmin and Trypsin on Polymeric Fibrin.” Ukr. Biokhim. Zh., 64(3): 14-20 (1992). Anonick, P. et al., “Regulation of Plasmin, Miniplasmin and (86). PCT No.: PCT/US2OOS/O13562 Streptokinase-Plasmin Complex by-O.--Antiplasmin, O.-- S371 (c)(1) Macroglobulin, and Antithrombin III in the Presence of Heparin.” . Thrombosis Res., 59: 449-462 (1990). (2), (4) Date: Feb. 1, 2008 Bennett, D., et al., “Kinetic Characterization of the Interaction of Biotinylated Human Interleukin 5 with an Fc Chimera of its Receptor (87) PCT Pub.
    [Show full text]
  • Cloning of Receptor Tyrosine Kinases from Anvsia
    Cloning of Receptor Tyrosine Kinases From ANvsia Jonathan Hislop Neurology and Neurosurgery, McGill University, Montreal. August, 1998 A thesis submitted to the Faculty of Graduate Studies and Research in partial fulfillment of the requirements of the degree of Master of Science @Jonathan Hislop, 1998 National Library Biblioth$ue nationale du Cana a Acquisitions and Acquisitions et Bibbgraphic Semices m~icesbibliographiques 395 Wdlngton Street 395, rue Weilinglori OItawaON K1AW OnawaON K1AON4 CariPds Canada The author has granted a non- L'auteur a accordé une licence non exclusive licence ailowing the exclusive permettant a la National Library of Canada to Bibliothèque nationale du Canada de reproduce, loan, distribute or seU reproduire, prêter, distribuer ou copies of this thesis in rnicrofonn, vendre des copies de cette thèse sous paper or electronic formats. la forme de microfiche/film, de reproduction sur papier ou sur format électronique. The author retains ownership of the L'auteur conserve la propriété du copyright in this thesis. Neither the droit d'auteur qui protège cette thèse. thesis nor substaatial extracts fkom it Ni la thèse ni des extraits substantiels may be printed or othenirise de celle-ci ne doivent être imprimes reproduced without the author's ou autrement reproduits sans son permission. autorisation. Abstract I have cloned two putative receptor tyrosine kinases (RTKs) fiom Aplysia californica, designated Aror and Anif. Aror is homologous to RTKs fiom the Ror subfarnily. Furthemore, Aror contains an extracellular immunoglobulin-like domain, cysteine-rich region, and kringie domain. These domains are d characteristic of Ror recepton. Amf is homologous to members of the Ret and FGF receptor subfamilies of RTKs.
    [Show full text]
  • The Molecular Basis of Blood Coagulation Review
    Cell, Vol. 53, 505-518, May 20, 1988, Copyright 0 1988 by Cell Press The Molecular Basis Review of Blood Coagulation Bruce Furie and Barbara C. Furie into the fibrin polymer. The clot, formed after tissue injury, Center for Hemostasis and Thrombosis Research is composed of activated platelets and fibrin. The clot Division of Hematology/Oncology mechanically impedes the flow of blood from the injured Departments of Medicine and Biochemistry vessel and minimizes blood loss from the wound. Once a New England Medical Center stable clot has formed, wound healing ensues. The clot is and Tufts University School of Medicine gradually dissolved by enzymes of the fibrinolytic system. Boston, Massachusetts 02111 Blood coagulation may be initiated through either the in- trinsic pathway, where all of the protein components are present in blood, or the extrinsic pathway, where the cell- Overview membrane protein tissue factor plays a critical role. Initia- tion of the intrinsic pathway of blood coagulation involves Blood coagulation is a host defense system that assists in the activation of factor XII to factor Xlla (see Figure lA), maintaining the integrity of the closed, high-pressure a reaction that is promoted by certain surfaces such as mammalian circulatory system after blood vessel injury. glass or collagen. Although kallikrein is capable of factor After initiation of clotting, the sequential activation of cer- XII activation, the particular protease involved in factor XII tain plasma proenzymes to their enzyme forms proceeds activation physiologically is unknown. The collagen that through either the intrinsic or extrinsic pathway of blood becomes exposed in the subendothelium after vessel coagulation (Figure 1A) (Davie and Fiatnoff, 1964; Mac- damage may provide the negatively charged surface re- Farlane, 1964).
    [Show full text]
  • Differential Binding of Plasminogen, Plasmin, and Angiostatin4.5 to Cell Surface B-Actin: Implications for Cancer-Mediated Angiogenesis
    Research Article Differential Binding of Plasminogen, Plasmin, and Angiostatin4.5 to Cell Surface B-Actin: Implications for Cancer-Mediated Angiogenesis Hao Wang,1 Jennifer A. Doll,1 Keyi Jiang,1 Deborah L. Cundiff,1 Jarema S. Czarnecki,1 Mindy Wilson,2 Karen M. Ridge,2 and Gerald A. Soff1,3 1Division of Hematology/Oncology and 2Division of Pulmonary and Critical Care Medicine, Department of Medicine and Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, Illinois and 3Division of Hematology/ Oncology, State University of New York Downstate Medical Center, Brooklyn, New York Abstract Several angiostatin isoforms have been reported, differing in Angiostatin4.5 (AS4.5) is the product of plasmin autoproteol- kringle content. Angiostatins consisting of plasminogen kringles 1 f to 3, kringles 1 to 4, or angiostatin4.5 (AS4.5), which includes ysis and consists of kringles 1 to 4 and 85% of kringle 5. In 78 529 culture, cancer cell surface globular B-actin mediates plasmin kringles 1 to 4 plus 85% of kringle 5 (Lys -Arg ), have been autoproteolysis to AS4.5. We now show that plasminogen generated in vitro by a variety of proteinases. However, it is still not binds to prostate cancer cells and that the binding colocalizes well understood which angiostatin isoforms are present naturally with surface B-actin, but AS4.5 does not bind to the cell in the human body (5, 8–13). We have shown previously that surface. Plasminogen and plasmin bind to immobilized AS4.5 is a naturally occurring human form (14). AS4.5 is generated B-actin similarly, with a K of f140 nmol/L.
    [Show full text]
  • Supplementary Materials
    Supplementary Materials 0.3 0.274 0.28 0.2735 0.26 0.273 0.24 0.2725 0.22 0.2 0.272 ccTM−score 0.18 0.2715 0.16 0.271 0.14 0.2705 0.12 0.1 0.27 1 2 3 4 5 6 7 8 9 10 0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 d gap penalty cut Figure S1. Selection of the optimal values for dcut and gap penalty. The experiments were done on 50% randomly selected groups from the SABmark_twi dataset. The gap penalty on the left panel is 0 and the dcut on the right panel is 4. 1 0.9 0.8 PCC=0.94 0.7 0.6 0.5 0.4 ACC of the MSTA 0.3 0.2 0.1 0 0 0.2 0.4 0.6 0.8 1 ACC of the PSA Figure S2. The correlation between the accuracy of the PSA and the MSTA. The data used in this figure are available in Table S5. Table S1. The influence of TM-score normalization. TM-score_s/TM-score_b is the mean TM-score normalized by the size of the smaller/bigger protein. ccTM-score_s and ccTM-score_b are the mean common core TM-scores of the corresponding MSTA. Dataset HOMSTRAD SABmark_sup SABmark_twi SISY-multiple Number of groups 398 425 209 86 Mean length difference 17.5 34.1 43.4 65.2 Pairwise TM-score_s 0.810 0.683 0.575 0.692 Pairwise TM-score_b 0.756 0.597 0.476 0.571 No.
    [Show full text]