DOCSLIB.ORG

Identification of Novel Molecular-Genetic Pathways Regulating the Development of Subpallial Derivatives

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Identification of Novel Molecular-Genetic Pathways Regulating the Development of Subpallial Derivatives University of Pennsylvania ScholarlyCommons Publicly Accessible Penn Dissertations 2016 Identification Of Novel Molecular-Genetic Pathways Regulating The Development Of Subpallial Derivatives David Tischfield University of Pennsylvania, [email protected] Follow this and additional works at: https://repository.upenn.edu/edissertations Part of the Genetics Commons, Molecular Biology Commons, and the Neuroscience and Neurobiology Commons Recommended Citation Tischfield, David, "Identification Of Novel Molecular-Genetic Pathways Regulating The Development Of Subpallial Derivatives" (2016). Publicly Accessible Penn Dissertations. 2611. https://repository.upenn.edu/edissertations/2611 This paper is posted at ScholarlyCommons. https://repository.upenn.edu/edissertations/2611 For more information, please contact [email protected]. Identification Of Novel Molecular-Genetic Pathways Regulating The Development Of Subpallial Derivatives Abstract The embryonic subpallium produces many different neuronal cell types present throughout the adult telencephalon, including striatal medium spiny neurons (MSN) and cortical interneurons. Dysfunction of either cell type leads to neurological and psychiatric disorders including schizophrenia, epilepsy, and Tourette’s syndrome. Thus, understanding the molecular pathways that regulate their development and function has important implications for understanding disease pathogenesis. This work describes novel methods and genetic factors that expand our ability to characterize the development and function of two major subpallial derivatives: cortical interneurons and striatal MSN. The first part of this thesis characterizes a novel enrichment method for producing parvalbumin-expressing (PV) interneurons from mouse embryonic stem cells. This method, which uses an atypical protein kinase C inhibitor to enhance intermediate neurogenesis, results in a markedly increased ratio of PV+ to somatostatin-expressing interneurons. The findings suggest that the mode of neurogenesis influences cortical interneuron fate determination. Moreover, PV+ interneurons can now be generated in large numbers to study their development, screen for factors that affect their physiology, and used in therapeutic applications. The second part of this thesis examines the function of two putative transcription factors, Zswim5 and Zswim6, in the regulation of striatal development. We show that these genes are expressed in subpallial precursors, and in the case of Zswim6, expressed in the adult striatum. Next, through the generation of Zswim5 and Zswim6 knockout mice, we provide a detailed anatomical, molecular, and behavioral characterization of the resulting phenotypes. Our findings er veal that loss of Zswim6 causes a reduction in striatal volume and morphological changes in MSN. Additionally, these structural changes are associated with alterations in motor behaviors including hyperactivity, impaired rotarod performance, and hyperresponsiveness to amphetamine. These results demonstrate that Zswim6 is indispensable for normal brain development and support findings in human genome-wide association studies that implicate Zswim6 with schizophrenia. Collectively, this dissertation provides novel insights into telencephalic development through the development of in vitro stem cell systems and in vivo disease mouse models that further our ability to test and understand neurological diseases. Degree Type Dissertation Degree Name Doctor of Philosophy (PhD) Graduate Group Neuroscience First Advisor Stewart A. Anderson Keywords Brain, Development, Interneurons, Zswim6 Subject Categories Genetics | Molecular Biology | Neuroscience and Neurobiology This dissertation is available at ScholarlyCommons: https://repository.upenn.edu/edissertations/2611 IDENTIFICATION OF NOVEL MOLECULAR-GENETIC PATHWAYS REGULATING THE DEVELOPMENT OF SUBPALLIAL DERIVATIVES David Tischfield A DISSERTATION in Neuroscience Presented to the Faculties of the University of Pennsylvania in Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy 2016 Supervisor of Dissertation Graduate Group Chairperson ____________________ _______________________ Stewart A. Anderson, MD. Joshua Gold, Ph.D. Associate Professor of Psychiatry Professor of Neuroscience Dissertation Committee Douglas J. Epstein, Ph.D. Professor of Genetics Wenqin Luo, M.D. Ph.D. Assistant Professor of Neuroscience Marc Fuccillo, M.D., Ph.D. Assistant Professor of Neuroscience IDENTIFICATION OF NOVEL MOLECULAR-GENETIC PATHWAYS REGULATING THE DEVELOPMENT OF SUBPALLIAL DERIVATIVES COPYRIGHT 2016 David James Tischfield This work is licensed under the Creative Commons Attribution- NonCommercial-ShareAlike 3.0 License To view a copy of this license, visit http://creativecommons.org/licenses/by-ny-sa/2.0/ This dissertation is dedicated to my brothers, Max and Sam – the two best friends and scientific compadres a guy could ask for. iii ACKNOWLEDGEMENTS This work was funded by R01 MH066912-01 and F30 MH105045-02. This research was also made possible in part due to Florin Tuluc and Eric Reidel at the Children’s Hospital of Philadelphia FACS core facility. I would also like to thank members of the Anderson lab, both past and present for helpful discussions and technical assistance. I would especially like to thank my mentor, Stewart Anderson, for allowing me to work so independently on almost anything I thought worthwhile, which allowed me to grow considerably as an experimentalist and critical thinker. To all the members of my thesis committee who helped me along the way. I'd also like to thank Jennifer Tyson, who was both a scientific mentor and close friend to me throughout my PhD. Also Erik Deboer and Sean Ryan, whose presence in lab made everything that much better. Shane Fitzgerald, for being a rock solid laboratory technician, hard worker, and all around good person. Ivor Asztalos, whose aptitude for statistics saved me. To the love of my life, Jillian and her cat Monster, who patiently stood by me during all of the ups and downs that a PhD entails. And lastly, to my family, but not just for the typical reasons. Thank you to my father Jay, who literally helped me get the resources and equipment that I needed at times to do my research. Thank you to my brothers, Max and Sam, both of whom helped me numerous times throughout my PhD to analyze data, think about my projects, and provide moral support. To my extremely talented sister-in-law Victoria Abraira, who was always willing to help me with my research in any way possible. To my mother, whose jovial spirit was always welcome. And to all of my friends not listed here who have made the last 6 years a great 6 years. Thank you. iv ABSTRACT IDENTIFICATION OF NOVEL MOLECULAR-GENETIC PATHWAYS REGULATING THE DEVELOPMENT OF SUBPALLIAL DERIVATIVES David Tischfield Dr. Stewart Anderson The embryonic subpallium produces many different neuronal cell types present throughout the adult telencephalon, including striatal medium spiny neurons (MSN) and cortical interneurons. Dysfunction of either cell type leads to neurological and psychiatric disorders including schizophrenia, epilepsy, and Tourette’s syndrome. Thus, understanding the molecular pathways that regulate their development and function has important implications for understanding disease pathogenesis. This work describes novel methods and genetic factors that expand our ability to characterize the development and function of two major subpallial derivatives: cortical interneurons and striatal MSN. The first part of this thesis characterizes a novel enrichment method for producing parvalbumin- expressing (PV) interneurons from mouse embryonic stem cells. This method, which uses an atypical protein kinase C inhibitor to enhance intermediate neurogenesis, results in a markedly increased ratio of PV+ to somatostatin- v expressing interneurons. The findings suggest that the mode of neurogenesis influences cortical interneuron fate determination. Moreover, PV+ interneurons can now be generated in large numbers to study their development, screen for factors that affect their physiology, and used in therapeutic applications. The second part of this thesis examines the function of two putative transcription factors, Zswim5 and Zswim6, in the regulation of striatal development. We show that these genes are expressed in subpallial precursors, and in the case of Zswim6, expressed in the adult striatum. Next, through the generation of Zswim5 and Zswim6 knockout mice, we provide a detailed anatomical, molecular, and behavioral characterization of the resulting phenotypes. Our findings reveal that loss of Zswim6 causes a reduction in striatal volume and morphological changes in MSN. Additionally, these structural changes are associated with alterations in motor behaviors including hyperactivity, impaired rotarod performance, and hyperresponsiveness to amphetamine. These results demonstrate that Zswim6 is indispensable for normal brain development and support findings in human genome-wide association studies that implicate Zswim6 with schizophrenia. Collectively, this dissertation provides novel insights into telencephalic development through the development of in vitro stem cell systems and in vivo disease mouse models that further our ability to test and understand neurological diseases. vi TABLE OF CONTENTS ACKNOWLEDGMENTS……………………………………………………………….iv ABSTRACT……………………………………………………………………………...v TABLE OF CONTENTS………………………………………………………….......vii LIST OF TABLES……………………………………………………………………….x LIST OF FIGURES………………………………………………………....................xi
Load more

Recommended publications
  • Endocrinology
    Endocrinology INTRODUCTION Endocrinology 1. Endocrinology is the study of the endocrine system secretions and their role at target cells within the body and nervous system are the major contributors to the flow of information between different cells and tissues. 2. Two systems maintain Homeostasis a. b 3. Maintain a complicated relationship 4. Hormones 1. The endocrine system uses hormones (chemical messengers/neurotransmitters) to convey information between different tissues. 2. Transport via the bloodstream to target cells within the body. It is here they bind to receptors on the cell surface. 3. Non-nutritive Endocrine System- Consists of a variety of glands working together. 1. Paracrine Effect (CHEMICAL) Endocrinology Spring 2013 Page 1 a. Autocrine Effect i. Hormones released by cells that act on the membrane receptor ii. When a hormone is released by a cell and acts on the receptors located WITHIN the same cell. Endocrine Secretions: 1. Secretions secreted Exocrine Secretion: 1. Secretion which come from a gland 2. The secretion will be released into a specific location Nervous System vs tHe Endocrine System 1. Nervous System a. Neurons b. Homeostatic control of the body achieved in conjunction with the endocrine system c. Maintain d. This system will have direct contact with the cells to be affected e. Composed of both the somatic and autonomic systems (sympathetic and parasympathetic) Endocrinology Spring 2013 Page 2 2. Endocrine System a. b. c. 3. Neuroendocrine: a. These are specialized neurons that release chemicals that travel through the vascular system and interact with target tissue. b. Hypothalamus à posterior pituitary gland History of tHe Endocrine System Bertold (1849)-FATHER OF ENDOCRINOLOGY 1.
    [Show full text]
  • Segregating Expression Domains of Two Goosecoid Genes During the Transition from Gastrulation to Neurulation in Chick Embryos
    Development 124, 1443-1452 (1997) 1443 Printed in Great Britain © The Company of Biologists Limited 1997 DEV2146 Segregating expression domains of two goosecoid genes during the transition from gastrulation to neurulation in chick embryos Lydia Lemaire1, Tobias Roeser1, Juan Carlos Izpisúa-Belmonte2 and Michael Kessel1,* 1Max-Planck-Institut für biophysikalische Chemie, Am Fassberg, D-37077 Göttingen, Germany 2The Salk Institute, 10010 N. Torrey Pines Road, La Jolla, California 92037, USA *Author for correspondence (e-mail: [email protected]) SUMMARY We report the isolation and characterization of a chicken plate around the anterior streak and overlying the pre- gene, GSX, containing a homeobox similar to that of the chordal plate. We demonstrate that the GSX-positive part goosecoid gene. The structure of the GSX gene and the of the primitive streak induces gastrulation, while the GSC- deduced GSX protein are highly related to the previously expressing part induces neurulation. After full extension of described goosecoid gene. The two homeodomains are 74% the streak, the fate of cells now characterized by GSX is to identical. In the first few hours of chick embryogenesis, the undergo neurulation, while those expressing GSC undergo expression pattern of GSX is similar to GSC, in the gastrulation. We discuss the effect of a duplicated basic posterior margin of the embryo and the young primitive goosecoid identity for the generation of a chordate nervous streak. Later during gastrulation, expression of the two system in ontogeny and phylogeny. genes segregate. GSC is expressed in the anterior part of the primitive streak, then in the node, and finally in the pre- chordal plate.
    [Show full text]
  • Title of Dissertation Goes Here in All Caps
    GENOME-WIDE ANALYSIS OF TRANSCRIPTION FACTORS ASCL1 AND PTF1A IN DEVELOPMENT AND CANCER APPROVED BY SUPERVISORY COMMITTEE Jane E. Johnson, Ph.D. Gang. Yu, Ph.D. Q. Richard Lu, Ph.D. Tae-Kyung Kim, Ph.D. DEDICATION I dedicate this to my mother and wife, for their love and devotion, and their endless support throughout my life. GENOME-WIDE ANALYSIS OF TRANSCRIPTION FACTORS ASCL1 AND PTF1A IN DEVELOPMENT AND CANCER by MARK DOMINIC BORROMEO DISSERTATION Presented to the Faculty of the Graduate School of Biomedical Sciences The University of Texas Southwestern Medical Center at Dallas In Partial Fulfillment of the Requirements For the Degree of DOCTOR OF PHILOSOPHY The University of Texas Southwestern Medical Center at Dallas Dallas, Texas December, 2013 Copyright by Mark Dominic Borromeo, 2013 All Rights Reserved GENOME-WIDE ANALYSIS OF TRANSCRIPTION FACTORS ASCL1 AND PTF1A IN DEVELOPMENT AND CANCER Mark Dominic Borromeo, Ph.D. The University of Texas Southwestern Medical Center at Dallas, 2013 Jane E. Johnson, Ph.D. Cell fate specification in the developing embryo relies on combinations of transcription factors to regulate tissue specific gene programs. Many of the same transcription factors can be found in multiple tissue types and are crucial for their development, and at other times these same factors can be misused in disease states. The basic helix-loop-helix (bHLH) factors Ascl1 and Ptf1a are examples of factors that give rise to and function in multiple tissues. Ascl1 and Ptf1a are essential for generating the correct number and sub-type of neurons in multiple regions of the nervous system. In addition, Ptf1a is required in the developing pancreas for both its formation and maturation, while Ascl1 is crucial for tumor v growth in malignant small cell lung carcinoma (SCLC).
    [Show full text]
  • Breakup of a Homeobox Cluster After Genome Duplication in Teleosts
    Breakup of a homeobox cluster after genome duplication in teleosts John F. Mulley*, Chi-hua Chiu†, and Peter W. H. Holland*‡ *Department of Zoology, University of Oxford, South Parks Road, Oxford, OX1 3PS, United Kingdom; and †Rutgers University, Department of Genetics, Life Sciences Building, Piscataway, NJ 08854 Edited by Eric H. Davidson, California Institute of Technology, Pasadena, CA, and approved May 11, 2006 (received for review January 13, 2006) Several families of homeobox genes are arranged in genomic been active throughout vertebrate history, we show that in the clusters in metazoan genomes, including the Hox, ParaHox, NK, ray-finned fish clade, the ParaHox gene cluster was lost in the Rhox, and Iroquois gene clusters. The selective pressures respon- evolution of teleosts after divergence from more basal ray- sible for maintenance of these gene clusters are poorly under- finned fish. stood. The ParaHox gene cluster is evolutionarily conserved be- tween amphioxus and human but is fragmented in teleost fishes. Results We show that two basal ray-finned fish, Polypterus and Amia, each We searched the emerging genome sequences of zebrafish possess an intact ParaHox cluster; this implies that the selective (Danio rerio; www.sanger.ac.uk͞Projects͞D࿝rerio) and two pressure maintaining clustering was lost after whole-genome pufferfish [Tetraodon nigroviridis (10) and Takifugu rubripes duplication in teleosts. Cluster breakup is because of gene loss, not (11)] for DNA sequences assignable to the Gsx, Xlox, and Cdx transposition or inversion, and the total number of ParaHox genes gene families. Comparison between species gave a consistent is the same in teleosts, human, mouse, and frog.
    [Show full text]
  • Septal Contributions to Olfactory Bulb Interneuron Diversity in the Embryonic Mouse Telencephalon: Role of the Homeobox Gene Gsx2 Shenyue Qin1,2, Stephanie M
    Qin et al. Neural Development (2017) 12:13 DOI 10.1186/s13064-017-0090-5 RESEARCH ARTICLE Open Access Septal contributions to olfactory bulb interneuron diversity in the embryonic mouse telencephalon: role of the homeobox gene Gsx2 Shenyue Qin1,2, Stephanie M. Ware5, Ronald R. Waclaw1,4 and Kenneth Campbell1,3* Abstract Background: Olfactory bulb (OB) interneurons are known to represent diverse neuronal subtypes, which are thought to originate from a number of telencephalic regions including the embryonic dorsal lateral ganglionic eminence (dLGE) and septum. These cells migrate rostrally toward the OB, where they then radially migrate to populate different OB layers including the granule cell layer (GCL) and the outer glomerular layer (GL). Although previous studies have attempted to investigate regional contributions to OB interneuron diversity, few genetic tools have been used to address this question at embryonic time points when the earliest populations are specified. Methods: In this study, we utilized Zic3-lacZ and Gsx2e-CIE transgenic mice as genetic fate-mapping tools to study OB interneuron contributions derived from septum and LGE, respectively. Moreover, to address the regional (i.e. septal) requirements of the homeobox gene Gsx2 for OB interneuron diversity, we conditionally inactivated Gsx2 in the septum, leaving it largely intact in the dLGE, by recombining the Gsx2 floxed allele using Olig2Cre/+ mice. Results: Our fate mapping studies demonstrated that the dLGE and septum gave rise to OB interneuron subtypes differently. Notably, the embryonic septum was found to give rise largely to the calretinin+ (CR+) GL subtype, while the dLGE was more diverse, generating all major GL subpopulations as well as many GCL interneurons.
    [Show full text]
  • Early Transcriptional Targets of Myod Link Myogenesis and Somitogenesis
    Developmental Biology 371 (2012) 256–268 Contents lists available at SciVerse ScienceDirect Developmental Biology journal homepage: www.elsevier.com/locate/developmentalbiology Early transcriptional targets of MyoD link myogenesis and somitogenesis Richard J. Maguire, Harry V. Isaacs, Mary Elizabeth Pownall n Biology Department, University of York, Heslington, York, North Yorkshire YO10 5YW, United Kingdom article info abstract Article history: In order to identify early transcriptional targets of MyoD prior to skeletal muscle differentiation, we Received 27 February 2012 have undertaken a transcriptomic analysis on gastrula stage Xenopus embryos in which MyoD has been Received in revised form knocked-down. Our validated list of genes transcriptionally regulated by MyoD includes Esr1 and Esr2, 10 July 2012 which are known targets of Notch signalling, and Tbx6, mesogenin, and FoxC1; these genes are all are Accepted 22 August 2012 known to be essential for normal somitogenesis but are expressed surprisingly early in the mesoderm. Available online 31 August 2012 In addition we found that MyoD is required for the expression of myf5 in the early mesoderm, in Keywords: contrast to the reverse relationship of these two regulators in amniote somites. These data highlight a Skeletal muscle role for MyoD in the early mesoderm in regulating a set of genes that are essential for both myogenesis Gene regulation and somitogenesis. Muscle progenitors & 2012 Elsevier Inc. All rights reserved. Determination Introduction gastrula embryo requires continued cell signals, such as FGF4, to maintain a myogenic fate (Standley et al., 2001), however, a single In vertebrates, the myogenic regulatory genes myoD, myf5, cell taken from a late gastrula embryo behaves as a determined myogenin, and mrf4 code for bHLH transcription factors which are myoblast: when transplanted to a ventral region, it differentiates expressed specifically in the myogenic cell lineage.
    [Show full text]
  • (12) United States Patent (10) Patent No.: US 8,377,886 B2 Susztak Et Al
    US008377886B2 (12) United States Patent (10) Patent No.: US 8,377,886 B2 Susztak et al. (45) Date of Patent: Feb. 19, 2013 (54) USE OF GAMMA SECRETASE INHIBITORS 7,144.910 B2 12/2006 Madin et al. AND NOTCH PATHWAY INHIBITORS FOR E.R. 358 (SR." TREATMENT AND PREVENTION OF RENAL 2003/0166894 A1* 9/2003 Kapeller Libermann et al. .......... 536,231 DISEASE 2006/0264380 A1* 11/2006 Hellstrom et al. .............. 514, 19 2007/0066568 A1 3/2007 Dalton et al. (75) Inventors: Katalin Susztak, Cresskill, NJ (US); Bernhard Bielesz, Rye, NY (US); FOREIGN PATENT DOCUMENTS Thiruvur G. Niranjan, Bronx, NY (US) WO WO2004/073630 * 9/2004 (73) Assignee: Albert Einstein College of Medicine of OTHER PUBLICATIONS Yeshiva University, Bronx, NY (US) “Glomerulonephritis' (in WWW. intellihealth.com/ IH/ht?t=31198& p=~br, IHWI-st, 24479-r, WSIH (*) Notice: Subject to any disclaimer, the term of this W000-b.* liprevent).* patent is extended or adjusted under 35 Vanes et al. in Nature 435(16), pp. 959-963 (2005).* U.S.C. 154(b) by 78 days. Masuda et al. in American Journal of Pathology, 159(2) (2001).* Yum et al. in Human Pathology 15(10), 921-927 (1984).* PCT International Preliminary Report on Patentability (dated Mar. (21) Appl. No.: 12/733,339 16, 2010) in connection with PCT International Patent Application No. PCT/US2003/010362, 6 pages. (22) PCT Filed: Sep. 4, 2008 Cheng HT et al., entitled Notch2, but not Notch1, is required for proximal fate acquisition in the mammalian nephron, Development (86) PCT NO.: PCT/US2O08/O10362 134,801-811 (2007).
    [Show full text]
  • Molecular Control of Neurogenesis: Aview from the Mammalian Cerebral Cortex
    Downloaded from http://cshperspectives.cshlp.org/ on October 1, 2021 - Published by Cold Spring Harbor Laboratory Press Molecular Control of Neurogenesis: AView from the Mammalian Cerebral Cortex Ben Martynoga, Daniela Drechsel, and Franc¸ois Guillemot Division of Molecular Neurobiology, National Institute for Medical Research, Mill Hill, London NW71AA, United Kingdom Correspondence: [email protected] SUMMARY The mammalian nervous system is the most complex organ of any living organism. How this complexity is generated during neural development is just beginning to be elucidated. This article discusses the signaling, transcriptional, and epigenetic mechanisms that are involved in neural development. The first part focuses on molecules that control neuronal numbers through regulation of the timing of onset of neurogenesis, the timing of the neuronal-to-glial switch, and the rate of progenitor proliferation. The second part focuses on molecules that control neuronal diversity by generating spatially or temporally distinct populations of neuro- nal progenitors. Most of the studies discussed in this article are focused on the developing mammalian cerebral cortex, because this is one of the main model systems for neural devel- opmental studies and many of the mechanisms identified in this tissue also operate elsewhere in the developing brain and spinal cord. Outline 1 Introduction 4 Concluding remarks 2 Controlling neuronal number References in the embryonic brain 3 Generating neuronal diversity in the embryonic brain Editors: Patrick P.L. Tam, W. James Nelson, and Janet Rossant Additional Perspectives on Mammalian Development available at www.cshperspectives.org Copyright # 2012 Cold Spring Harbor Laboratory Press; all rights reserved; doi: 10.1101/cshperspect.a008359 Cite this article as Cold Spring Harb Perspect Biol 2012;4:a008359 1 Downloaded from http://cshperspectives.cshlp.org/ on October 1, 2021 - Published by Cold Spring Harbor Laboratory Press B.
    [Show full text]
  • BMC Biology Biomed Central
    BMC Biology BioMed Central Research article Open Access Classification and nomenclature of all human homeobox genes PeterWHHolland*†1, H Anne F Booth†1 and Elspeth A Bruford2 Address: 1Department of Zoology, University of Oxford, South Parks Road, Oxford, OX1 3PS, UK and 2HUGO Gene Nomenclature Committee, European Bioinformatics Institute (EMBL-EBI), Wellcome Trust Genome Campus, Hinxton, Cambridgeshire, CB10 1SA, UK Email: Peter WH Holland* - [email protected]; H Anne F Booth - [email protected]; Elspeth A Bruford - [email protected] * Corresponding author †Equal contributors Published: 26 October 2007 Received: 30 March 2007 Accepted: 26 October 2007 BMC Biology 2007, 5:47 doi:10.1186/1741-7007-5-47 This article is available from: http://www.biomedcentral.com/1741-7007/5/47 © 2007 Holland 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: The homeobox genes are a large and diverse group of genes, many of which play important roles in the embryonic development of animals. Increasingly, homeobox genes are being compared between genomes in an attempt to understand the evolution of animal development. Despite their importance, the full diversity of human homeobox genes has not previously been described. Results: We have identified all homeobox genes and pseudogenes in the euchromatic regions of the human genome, finding many unannotated, incorrectly annotated, unnamed, misnamed or misclassified genes and pseudogenes.
    [Show full text]
  • ABC Transporters in Cancer Stem Cells: Beyond Chemoresistance
    International Journal of Molecular Sciences Review ABC Transporters in Cancer Stem Cells: Beyond Chemoresistance Romana-Rea Begicevic and Marco Falasca * ID Metabolic Signalling Group, School of Biomedical Sciences, Curtin Health Innovation Research Institute, Curtin University, Perth WA 6102, Australia; [email protected] * Correspondence: [email protected]; Tel.: +61-08-9266-9712 Received: 16 October 2017; Accepted: 2 November 2017; Published: 8 November 2017 Abstract: The efficacy of chemotherapy is one of the main challenges in cancer treatment and one of the major obstacles to overcome in achieving lasting remission and a definitive cure in patients with cancer is the emergence of cancer resistance. Indeed, drug resistance is ultimately accountable for poor treatment outcomes and tumour relapse. There are various molecular mechanisms involved in multidrug resistance, such as the change in the activity of membrane transporters primarily belonging to the ATP binding cassette (ABC) transporter family. In addition, it has been proposed that this common feature could be attributed to a subpopulation of slow-cycling cancer stem cells (CSCs), endowed with enhanced tumorigenic potential and multidrug resistance. CSCs are characterized by the overexpression of specific surface markers that vary in different cancer cell types. Overexpression of ABC transporters has been reported in several cancers and more predominantly in CSCs. While the major focus on the role played by ABC transporters in cancer is polarized by their involvement in chemoresistance, emerging evidence supports a more active role of these proteins, in which they release specific bioactive molecules in the extracellular milieu. This review will outline our current understanding of the role played by ABC transporters in CSCs, how their expression is regulated and how they support the malignant metabolic phenotype.
    [Show full text]
  • Molecular Control of Development in the Reef Coral, Acropora Millepora
    Proceedings 9th International Coral Reef Symposium, Bali, Indonesia 23-27 October 2000 Molecular control of development in the reef coral, Acropora millepora E. E. Ball1, D. C. Hayward1, J. Catmull1,2, J. S. Reece-Hoyes1,2, N. R. Hislop1,2, P. L. Harrison3 and D. J. Miller2 ABSTRACT A brief overview of the embryonic and larval development of Acropora, including some previously unpublished data, provides the background for this review of our rapidly expanding knowledge of the genes that control early development in corals, with particular emphasis on Hox and Hox-like genes. Since the Phylum Cnidaria is widely accepted to be an ancient group of organisms, genes, and motifs within genes, that are shared by corals and higher metazoans are presumably ancient. Thus, shared genes allow us to study how gene structure and function have changed with time, while genes specific to higher metazoans have, presumably, evolved more recently. Anatomically, corals have many fewer cell types than higher metazoans, but it is not clear that this apparent simplicity will be reflected at the molecular level. We have already found Acropora representatives of structural genes, housekeeping genes, nuclear receptors, Hox-like genes, Pax genes and components of the dpp signalling pathway. However, thus far there is no unequivocal evidence for the cluster of Hox genes, known as the zootype genes, that is otherwise widespread among the Metazoa. As more data become available, the Cnidaria are making an increasing contribution to our knowledge of the evolution of gene structure, function, and regulation. We here illustrate the evolutionary approach that we are taking to the characterisation of coral genes with a review of our work on the Acropora Hox-like gene, cnox2-Am.
    [Show full text]
  • Safety Manual for Tms320f28002x User's Guide
    www.ti.com Table of Contents Functional Safety Information Safety Manual for TMS320F28002x ABSTRACT This document is a safety manual for the Texas Instruments TMS320F28002x safety critical real time microcontroller product family. The product family utilizes a common safety architecture that is implemented in multiple application-focused products. Table of Contents 1 Introduction.............................................................................................................................................................................3 2 TMS320F28002x Product Safety Capability and Constraints............................................................................................. 4 3 TI Development Process for Management of Systematic Faults....................................................................................... 4 3.1 TI New-Product Development Process.............................................................................................................................. 4 3.2 TI Safety Development Process.........................................................................................................................................5 4 TMS320F28002x Product Overview...................................................................................................................................... 7 4.1 C2000 Architecture and Product Overview........................................................................................................................ 7 4.2 Functional Safety Concept................................................................................................................................................
    [Show full text]