DOCSLIB.ORG

The Roles of the Dystrophin-Associated Glycoprotein Complex at the Synapse

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text

Load more

Mol Neurobiol (2010) 41:1–21 DOI 10.1007/s12035-009-8089-5 The Roles of the Dystrophin-Associated Glycoprotein Complex at the Synapse Gonneke S. K. Pilgram & Saranyapin Potikanond & Richard A. Baines & Lee G. Fradkin & Jasprina N. Noordermeer Received: 24 August 2009 /Accepted: 15 October 2009 /Published online: 9 November 2009 # The Author(s) 2009. This article is published with open access at Springerlink.com Abstract Duchenne muscular dystrophy is caused by muta- Keywords Dystrophin . DGC . NMJ . CNS . PNS . Retina . tions in the dystrophin gene and is characterized by Duchenne muscular dystrophy . Mammals . Drosophila . progressive muscle wasting. A number of Duchenne patients C. elegans also present with mental retardation. The dystrophin protein is part of the highly conserved dystrophin-associated glyco- Abbreviations protein complex (DGC) which accumulates at the neuromus- ACh Acetylcholine cular junction (NMJ) and at a variety of synapses in the AChR Acetylcholine receptor peripheral and central nervous systems. Many years of Akt Protein kinase B research into the roles of the DGC in muscle have revealed BMP Bone morphogenetic protein its structural function in stabilizing the sarcolemma. In Ca2+ Calcium ion addition, the DGC also acts as a scaffold for various signaling CaMKII Ca2+/calmodulin-dependent protein kinase II pathways. Here, we discuss recent advances in understanding cGMP Cyclic guanosine monophosphate DGC roles in the nervous system, gained from studies in both CNS Central nervous system vertebrate and invertebrate model systems. From these DGC Dystrophin-associated glycoprotein complex studies, it has become clear that the DGC is important for DMD Duchenne muscular dystrophy the maturation of neurotransmitter receptor complexes and for EPSP Excitatory postsynaptic potential the regulation of neurotransmitter release at the NMJ and ERG Electroretinogram central synapses. Furthermore, roles for the DGC have been GABA γ-Aminobutyric acid established in consolidation of long-term spatial and recog- Grb2 Growth factor receptor-bound protein 2 nition memory. The challenges ahead include the integration ILM Inner limiting membrane of the behavioral and mechanistic studies and the use of this InR Insulin receptor information to identify therapeutic targets. IPSC Inhibitory postsynaptic current IPSP Inhibitory postsynaptic potential Gonneke S. K. Pilgram and Saranyapin Potikanond contributed LTD Long-term depression equally to this work. LTP Long-term potentiation G. S. K. Pilgram : S. Potikanond : L. G. Fradkin (*) : MAPK Mitogen-activated protein kinase J. N. Noordermeer (*) mEPSP Miniature EPSP Laboratory of Developmental Neurobiology, Department mIPSC Miniature IPSC of Molecular and Cell Biology, Leiden University Medical Center, mIPSP Miniature IPSP Einthovenweg 20, P.O. Box 9600, 2300 RC Leiden, The Netherlands MuSK Muscle-specific kinase e-mail: [email protected] NMJ Neuromuscular junction e-mail: [email protected] nNOS Neuronal nitric oxide synthase NO Nitric oxide R. A. Baines Faculty of Life Sciences, University of Manchester, NOS Nitric oxide synthase Manchester M13 9PT, UK OPL Outer plexiform layer 2 Mol Neurobiol (2010) 41:1–21 PI3K Phosphoinositide 3-kinases containing a ZZ domain, and a highly conserved carboxy- PKA Protein kinase A terminal region including a coiled-coil domain. PKC Protein kinase C Dystrophin is predominantly expressed in the muscula- PKG Protein kinase G ture and the nervous system (Fig. 1, Table 2, and references POMT1/2 Protein O-mannosyltransferase 1 or 2 therein). More specifically, the three distinct Dp427 PPF Paired-pulse facilitation variants that are transcribed from different promoters and STD Short-term depression have distinct first exons are expressed in skeletal muscle STP Short-term potentiation (Dp427M), throughout the brain (Dp427B) and in Purkinje UGC Utrophin-associated glycoprotein complex cells (Dp427P), respectively. Dp260 is expressed in the utrn Utrophin retina, Dp140 in brain and kidney, Dp116 in the peripheral VNC Ventral nerve cord nervous system, and Dp71 is uniformly expressed, but most prominently present throughout the mammalian brain (reviewed in [7]; Fig. 1; Table 2). In mammals, there are two proteins which are significantly homologous to dystrophin, utrophin [8], and the much shorter dystrophin- Introduction related protein 2 (DRP2) [9]. Utrophin is more ubiquitously expressed compared to dystrophin, hence its name. It is Duchenne muscular dystrophy (DMD) is a common X- found in developing skeletal and smooth muscle, the linked, fatal genetic disorder characterized by progressive nervous system, the lung, kidney, liver, spleen, and stomach muscle wasting [1]. The disease was named after the [10, 11]. French neurologist G.B.A. Duchenne who, in the mid- Many components of the DGC have been identified, 1800s, described patients that suffered not only from including the dystrobrevins (DB-α and DB-β), the syntro- muscular dystrophy but also from mental retardation [2]. A phins (α1, β1, β2, γ1, and γ2), dystroglycan (DG-α/β), major advancement in understanding the underlying cause the sarcoglycans (SG-α, SG-β, SG-γ, SG-δ, SG-ε, and SG- of DMD came in 1987, when dystrophin was identified as ζ), and sarcospan [10, 12]. Together with dystrophin, these the protein that is absent in DMD patients [3, 4]. Mental proteins form a large, molecularly heterogeneous cluster retardation occurs in approximately one third of DMD [13], known as the DGC, that differs in composition patients and is apparently dependent on the specific depending on the tissue or organs where the components location of the mutation within the dystrophin gene (in are expressed (reviewed in [10, 14–16]; Fig. 1; Table 2). mammals called the DMD gene) [5]. Despite more than two The proteins of the DGC are highly conserved between decades of intense clinical and basic research into the DMD species, although there are fewer homologs and isoforms in disease process and the interactions and roles of the the lower vertebrates, such as zebrafish, and in the dystrophin protein, a cure for the disease remains elusive invertebrates, Caenorhabditis elegans and Drosophila and treatments palliative. Thus, much remains to be learned (Table 1). about the basic biological roles of the dystrophin protein in Due to the complex and variable composition of the the musculature and in the brain. DGC, it is difficult to assign a general function to this The DMD gene is one of the largest genes in the human transmembrane complex. However, in all organisms studied genome, spanning 2.3 Mb [6]. It has three upstream thus far, the different DGCs localize to the plasma promoters that control expression of full-length dystrophin membrane (reviewed in [12]). In muscle, the DGC has Dp427 and four internal promoters which regulate expres- long been thought to be required for the stabilization of the sion of the short dystrophin isoforms, Dp260, Dp140, plasma membrane by linking the actin cytoskeleton to the Dp116, and Dp71 (reviewed at www.dmd.nl; Table 1; extracellular matrix [17]. Disruption of the DGC caused by Textbox 1 in “Appendix”). The complexity of DMD gene the absence of dystrophin consequently renders the sarco- expression, which results in multiple transcripts and protein lemma susceptible to mechanical damage during contrac- isoforms, has made understanding the functions of individ- tion and ultimately results in muscle degeneration. More ual dystrophin protein isoforms difficult. Dp427 has an recently, it has been established that the DGC also functions amino-terminal actin-binding domain, and Dp427, Dp260, as a scaffold for proteins involved in signaling, including Dp140, and Dp116 have a variable number of spectrin-like neuronal nitric oxide synthase (nNOS), phosphoinositol repeats that are predicted to form triple-helical rod-like triphosphate 2, calmodulin, and growth factor receptor- structures. Dystrophin proteins invariably bear a number of bound protein 2 (grb2; reviewed in [18]). Additional protein–protein interaction domains, some of which are evidence supports the involvement of the DGC in the extra- bound by other dystrophin-associated glycoprotein complex cellular signal-regulated kinases (ERK)/mitogen-activated (DGC) members: a WW domain, a cysteine-rich region protein kinase (MAPK) signaling cascade [19], epidermal Mol Neurobiol (2010) 41:1–21 3 Table 1 Compilation of the known DGC components in human/mice, zebrafish, C. elegans, and Drosophila DGC member Species Human/mice (www.dmd.nl) Zebrafish [180] C. elegans [33] Drosophila [32] Protein (gene) (www.zfin.org) (www.wormbase.org) (www.flybase.bio.indiana.edu) Dystrophin Long isoforms: Dp427 Long isoform: a 400-kD Dystrophin-like Long isoforms: DLP1-3 (M, B, P) dystrophin ortholog protein (dys-1) Short isoforms: Dp260, Short isoform: Dp71 Short isoforms: Dp205, Dp140, Dp116, Dp71 (DMD) (dmd) Dp186, Dp117 (Dys) Utrophin a-, b-, g-Utrophin (utrn) Utrophin (utrn) [181] DRP2 Dystrophin-related protein DRP2 [181] –– (DRP2) Dystrobrevin α-Dystrobrevin (DTNA) α-Dystrobrevin (dtna) Dystrobrevin (dyb-1) Dystrobrevin-like (Dyb) β-Dystrobrevin (DTNB) β-Dystrobrevin (dtnb) γ-Dystrobrevin (dtng) [181] Dystroglycan α/β-Dystroglycan (DAG1) α/β-Dystroglycan (dag1) Dystroglycan (dgn-1) Dystroglycan (Dg) Sarcoglycan α-, ε-, β-, γ-, δ-, α-, β-, δ-ε-, γ-, α-,β-, δ/γ- Sarcoglycan-α, Sarcoglycan-β, ζ-Sarcoglycan (SCGA-Z) ζ-Sarcoglycan Sarcoglycan Sarcoglycan-δ (Scgα, Scgβ, (α-, β-, δ/γ-sgn) Scgδ) Sarcospan Sarcospan (SSPN), Not determined –– (microspan
Recommended publications
  • Individual Protomers of a G Protein-Coupled Receptor Dimer Integrate Distinct Functional Modules

    Individual Protomers of a G Protein-Coupled Receptor Dimer Integrate Distinct Functional Modules

    OPEN Citation: Cell Discovery (2015) 1, 15011; doi:10.1038/celldisc.2015.11 © 2015 SIBS, CAS All rights reserved 2056-5968/15 ARTICLE www.nature.com/celldisc Individual protomers of a G protein-coupled receptor dimer integrate distinct functional modules Nathan D Camp1, Kyung-Soon Lee2, Jennifer L Wacker-Mhyre2, Timothy S Kountz2, Ji-Min Park2, Dorathy-Ann Harris2, Marianne Estrada2, Aaron Stewart2, Alejandro Wolf-Yadlin1, Chris Hague2 1Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA, USA; 2Department of Pharmacology, University of Washington School of Medicine, Seattle, WA, USA Recent advances in proteomic technology reveal G-protein-coupled receptors (GPCRs) are organized as large, macromolecular protein complexes in cell membranes, adding a new layer of intricacy to GPCR signaling. We previously reported the α1D-adrenergic receptor (ADRA1D)—a key regulator of cardiovascular, urinary and CNS function—binds the syntrophin family of PDZ domain proteins (SNTA, SNTB1, and SNTB2) through a C-terminal PDZ ligand inter- action, ensuring receptor plasma membrane localization and G-protein coupling. To assess the uniqueness of this novel GPCR complex, 23 human GPCRs containing Type I PDZ ligands were subjected to TAP/MS proteomic analysis. Syntrophins did not interact with any other GPCRs. Unexpectedly, a second PDZ domain protein, scribble (SCRIB), was detected in ADRA1D complexes. Biochemical, proteomic, and dynamic mass redistribution analyses indicate syntrophins and SCRIB compete for the PDZ ligand, simultaneously exist within an ADRA1D multimer, and impart divergent pharmacological properties to the complex. Our results reveal an unprecedented modular dimeric architecture for the ADRA1D in the cell membrane, providing unexpected opportunities for fine-tuning receptor function through novel protein interactions in vivo, and for intervening in signal transduction with small molecules that can stabilize or disrupt unique GPCR:PDZ protein interfaces.
  • Research Paper Expression of the Pokemon Gene and Pikachurin Protein in the Pokémon Pikachu

    Research Paper Expression of the Pokemon Gene and Pikachurin Protein in the Pokémon Pikachu

    Academia Journal of Scientific Research 8(7): 235-238, July 2020 DOI: 10.15413/ajsr.2020.0503 ISSN 2315-7712 ©2020 Academia Publishing Research Paper Expression of the pokemon gene and pikachurin protein in the pokémon pikachu Accepted 13th July, 2020 ABSTRACT The proto-oncogene Pokemon is typically over expressed in cancers, and the protein Pikachurin is associated with ribbon synapses in the retina. Studying the Samuel Oak1; Ganka Joy2 and Mattan Schlomi1* former is of interest in molecular oncology and the latter in the neurodevelopment of vision. We quantified the expression levels of Pokemon and Pikachurin in the 1Okido Institute, Pallet Town, Kanto, Japan. 2Department of Opthalmology, Tokiwa City Pokémon Pikachu, where the gene and protein both act as in other vertebrates. Pokémon Center, Viridian City, Kanto, Japan. The controversy over their naming remains an issue. *Corresponding author. E-mail: [email protected]. Tel: +81 3-3529-1821 Key words: Pikachurin, EGFLAM, fibronectin, pokemon, Zbtb7, Pikachu. INTRODUCTION Pokemon is a proto-oncogene discovered in 2005 (Maeda et confusing, they do avoid the controversies associated with al., 2005). It is a “master gene” for cancer: over expression naming a disease-related gene after adorable, child-friendly of Pokemon is positively associated with multiple different creatures. [For more information, consider the forms of cancer, and some hypothesize that its expression is holoprosencephaly-associated gene sonic hedgehog and the a prerequisite for subsequent oncogenes [cancer-causing molecule that inhibits it, Robotnikin (Stanton et al., 2009)]. genes] to actually cause cancer (Gupta et al., 2020). The The gene Pokemon is thus not to be confused with name stands for POK erythroid myeloid ontogenic factor.
  • The Amino Acid Sequence of Troponin C from Chicken Skeletal Muscle

    The Amino Acid Sequence of Troponin C from Chicken Skeletal Muscle

    View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Elsevier - Publisher Connector Volume 70, number 1 FEBS LETTERS November 1976 THE AMINO ACID SEQUENCE OF TROPONIN C FROM CHICKEN SKELETAL MUSCLE J. M. WILKINSON Department of Biochemistry, University of Birmingham, P. 0. Box 363, Birmingham, BI5 2TT. England Received 21 September 1976 1. Introduction Hirabayshi and Perry [5] have shown that chicken troponin C isolated from a mixture of breast and leg Troponin C is the component of the troponin muscle is a single antigen and hence, by inference the complex which binds Ca2+ and thereby triggers the troponin C components present in both tissues are activation of the actomyosin ATPase and hence the very similar if not identical. The present paper reports onset of contraction. The amino acid sequence of the amino acid sequence of chicken troponin C and troponin C from rabbit fast skeletal muscle has been discusses its relationship with rabbit troponin C to determined by Collins et al. [l ] and that from which it is very similar. No evidence of heterogeneity bovine cardiac muscle by van Eerd and Takahashi in the sequence has been found. [2]. These proteins have been shown to be homolo- gous not only with the calcium binding parvalbumins 2. Experimental but also with both the DTNB and alkali light chains of myosin [a]. Based on the homology with the Troponin C was prepared from mixed breast and parvalbumins, four binding sites for Ca2+ have been leg muscle and purified by chromatography on DEAE- proposed for rabbit troponin C and a three dimensio- cellulose as described by Perry and Cole 171.
  • Mouse Egflam Knockout Project (CRISPR/Cas9)

    Mouse Egflam Knockout Project (CRISPR/Cas9)

    https://www.alphaknockout.com Mouse Egflam Knockout Project (CRISPR/Cas9) Objective: To create a Egflam knockout Mouse model (C57BL/6J) by CRISPR/Cas-mediated genome engineering. Strategy summary: The Egflam gene (NCBI Reference Sequence: NM_001289496 ; Ensembl: ENSMUSG00000042961 ) is located on Mouse chromosome 15. 23 exons are identified, with the ATG start codon in exon 1 and the TAA stop codon in exon 23 (Transcript: ENSMUST00000096494). Exon 2~3 will be selected as target site. Cas9 and gRNA will be co-injected into fertilized eggs for KO Mouse production. The pups will be genotyped by PCR followed by sequencing analysis. Note: Homozygous null mutants are viable and fertile under normal conditions. They exhibit abnormal photoreceptor ribbon synapses, resulting in alteration in synaptic signal transmission and visual function. Exon 2 starts from about 3.21% of the coding region. Exon 2~3 covers 6.36% of the coding region. The size of effective KO region: ~1952 bp. The KO region does not have any other known gene. Page 1 of 9 https://www.alphaknockout.com Overview of the Targeting Strategy Wildtype allele 5' gRNA region gRNA region 3' 1 2 3 23 Legends Exon of mouse Egflam Knockout region Page 2 of 9 https://www.alphaknockout.com Overview of the Dot Plot (up) Window size: 15 bp Forward Reverse Complement Sequence 12 Note: The 2000 bp section upstream of Exon 2 is aligned with itself to determine if there are tandem repeats. No significant tandem repeat is found in the dot plot matrix. So this region is suitable for PCR screening or sequencing analysis.
  • Muscular Dystrophy in PTFR/Cavin-1 Null Mice

    Muscular Dystrophy in PTFR/Cavin-1 Null Mice

    Muscular dystrophy in PTFR/cavin-1 null mice Shi-Ying Ding, … , Libin Liu, Paul F. Pilch JCI Insight. 2017;2(5):e91023. https://doi.org/10.1172/jci.insight.91023. Research Article Cell biology Muscle biology Mice and humans lacking the caveolae component polymerase I transcription release factor (PTRF, also known as cavin- 1) exhibit lipo- and muscular dystrophy. Here we describe the molecular features underlying the muscle phenotype for PTRF/cavin-1 null mice. These animals had a decreased ability to exercise, and exhibited muscle hypertrophy with increased muscle fiber size and muscle mass due, in part, to constitutive activation of the Akt pathway. Their muscles were fibrotic and exhibited impaired membrane integrity accompanied by an apparent compensatory activation of the dystrophin-glycoprotein complex along with elevated expression of proteins involved in muscle repair function. Ptrf deletion also caused decreased mitochondrial function, oxygen consumption, and altered myofiber composition. Thus, in addition to compromised adipocyte-related physiology, the absence of PTRF/cavin-1 in mice caused a unique form of muscular dystrophy with a phenotype similar or identical to that seen in humans lacking this protein. Further understanding of this muscular dystrophy model will provide information relevant to the human situation and guidance for potential therapies. Find the latest version: https://jci.me/91023/pdf RESEARCH ARTICLE Muscular dystrophy in PTFR/cavin-1 null mice Shi-Ying Ding,1 Libin Liu,1 and Paul F. Pilch1,2 1Department of Biochemistry, 2Department of Medicine, Boston University School of Medicine, Boston, Massachusetts, USA. Mice and humans lacking the caveolae component polymerase I transcription release factor (PTRF, also known as cavin-1) exhibit lipo- and muscular dystrophy.
  • The Roles of A-Dystroglycan in the Central Nervous System- Man Qi Li1 and Yi Luo2*

    The Roles of A-Dystroglycan in the Central Nervous System- Man Qi Li1 and Yi Luo2*

    International Journal of Neurological Disorders Review Article The Roles of A-Dystroglycan in the Central Nervous System- Man Qi Li1 and Yi Luo2* 1Department of Foreign Language, Yangtze University College of Arts and Science, Jing zhou 434000, China 2Department of Neurology, The First People’s Hospital of Jingzhou, the First Affiliated Hospital of Yangtze University, Jing zhou 434000, China *Address for Correspondence: Yi Luo, Department of Neurology, The First People’s Hospital of Jingzhou, the First Affiliated Hospital of Yangtze University, Jing zhou 434000, China, E-mail: Submitted: 12 December 2019; Approved: 02 January 2020; Published: 04 January 2020 Cite this article: Li MQ, Luo Y. The Roles of Α-Dystroglycan in the Central Nervous System. Int J Neurol Dis. 2020;4(1): 001-004. Copyright: © 2020 Li MQ, et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. ISSN: 2639-7021 International Journal of Neurological Disorders ISSN: 2639-7021 ABSTRACT Dystroglycan is a membrane protein, which is related to extracellular matrix in various mammalian tissues. α-subunit of Dystroglycan (α-DG) is highly glycosylated, including a special O-mannose group, depending on this unique glycosylation to bind its ligands. Diff erent groups of muscular dystrophies are caused by a low glycosylation of α-DG, accompanied by the involvement of the central nervous system, from the brain malformation to intellectual retardation. More and more literatures discuss α-DG in the central nervous system, from the brain development to the maintenance of synapses.
  • Analysis of the Dystrophin Interactome

    Analysis of the Dystrophin Interactome

    Analysis of the dystrophin interactome Dissertation In fulfillment of the requirements for the degree “Doctor rerum naturalium (Dr. rer. nat.)” integrated in the International Graduate School for Myology MyoGrad in the Department for Biology, Chemistry and Pharmacy at the Freie Universität Berlin in Cotutelle Agreement with the Ecole Doctorale 515 “Complexité du Vivant” at the Université Pierre et Marie Curie Paris Submitted by Matthew Thorley born in Scunthorpe, United Kingdom Berlin, 2016 Supervisor: Simone Spuler Second examiner: Sigmar Stricker Date of defense: 7th December 2016 Dedicated to My mother, Joy Thorley My father, David Thorley My sister, Alexandra Thorley My fiancée, Vera Sakhno-Cortesi Acknowledgements First and foremost, I would like to thank my supervisors William Duddy and Stephanie Duguez who gave me this research opportunity. Through their combined knowledge of computational and practical expertise within the field and constant availability for any and all assistance I required, have made the research possible. Their overarching support, approachability and upbeat nature throughout, while granting me freedom have made this year project very enjoyable. The additional guidance and supported offered by Matthias Selbach and his team whenever required along with a constant welcoming invitation within their lab has been greatly appreciated. I thank MyoGrad for the collaboration established between UPMC and Freie University, creating the collaboration within this research project possible, and offering research experience in both the Institute of Myology in Paris and the Max Delbruck Centre in Berlin. Vital to this process have been Gisele Bonne, Heike Pascal, Lidia Dolle and Susanne Wissler who have aided in the often complex processes that I am still not sure I fully understand.
  • Dystroglycan Is a Scaffold for Extracellular Axon Guidance Decisions L Bailey Lindenmaier1, Nicolas Parmentier2, Caiying Guo3, Fadel Tissir2, Kevin M Wright1*

    Dystroglycan Is a Scaffold for Extracellular Axon Guidance Decisions L Bailey Lindenmaier1, Nicolas Parmentier2, Caiying Guo3, Fadel Tissir2, Kevin M Wright1*

    RESEARCH ARTICLE Dystroglycan is a scaffold for extracellular axon guidance decisions L Bailey Lindenmaier1, Nicolas Parmentier2, Caiying Guo3, Fadel Tissir2, Kevin M Wright1* 1Vollum Institute, Oregon Health & Science University, Portland, United States; 2Institiute of Neuroscience, Universite´ Catholique de Louvain, Brussels, Belgium; 3Janelia Research Campus, Howard Hughes Medical Institute, Ashburn, United States Abstract Axon guidance requires interactions between extracellular signaling molecules and transmembrane receptors, but how appropriate context-dependent decisions are coordinated outside the cell remains unclear. Here we show that the transmembrane glycoprotein Dystroglycan interacts with a changing set of environmental cues that regulate the trajectories of extending axons throughout the mammalian brain and spinal cord. Dystroglycan operates primarily as an extracellular scaffold during axon guidance, as it functions non-cell autonomously and does not require signaling through its intracellular domain. We identify the transmembrane receptor Celsr3/ Adgrc3 as a binding partner for Dystroglycan, and show that this interaction is critical for specific axon guidance events in vivo. These findings establish Dystroglycan as a multifunctional scaffold that coordinates extracellular matrix proteins, secreted cues, and transmembrane receptors to regulate axon guidance. DOI: https://doi.org/10.7554/eLife.42143.001 Introduction During neural circuit development, extending axons encounter distinct combinations of cues and *For correspondence: growth substrates that guide their trajectory. These cues can be attractive or repulsive, secreted [email protected] and/or anchored to cell membranes, and signal through cell surface receptors on the growth cones of axons (Kolodkin and Tessier-Lavigne, 2011). Receptors also recognize permissive and non-per- Competing interest: See missive growth substrates formed by the extracellular matrix (ECM), surrounding cells, and other page 21 axons (Raper and Mason, 2010).
  • Promoter Alteration Causes Transcriptional Repression of the POMGNT1 Gene in Limb-Girdle Muscular Dystrophy Type 2O

    Promoter Alteration Causes Transcriptional Repression of the POMGNT1 Gene in Limb-Girdle Muscular Dystrophy Type 2O

    European Journal of Human Genetics (2012) 20, 945–952 & 2012 Macmillan Publishers Limited All rights reserved 1018-4813/12 www.nature.com/ejhg ARTICLE Promoter alteration causes transcriptional repression of the POMGNT1 gene in limb-girdle muscular dystrophy type 2O Madalina Raducu1, Jonathan Baets2,3, Oihane Fano1, Rudy Van Coster4 and Jesu´s Cruces*,1 Limb-girdle muscular dystrophy type 2O (LGMD2O) belongs to a group of rare muscular dystrophies named dystroglycanopathies, which are characterized molecularly by hypoglycosylation of a-dystroglycan (a-DG). Here, we describe the first dystroglycanopathy patient carrying an alteration in the promoter region of the POMGNT1 gene (protein O-mannose b-1,2-N-acetylglucosaminyltransferase 1), which involves a homozygous 9-bp duplication (-83_-75dup). Analysis of the downstream effects of this mutation revealed a decrease in the expression of POMGNT1 mRNA and protein because of negative regulation of the POMGNT1 promoter by the transcription factor ZNF202 (zinc-finger protein 202). By functional analysis of various luciferase constructs, we localized a proximal POMGNT1 promoter and we found a 75% decrease in luciferase activity in the mutant construct when compared with the wild type. Electrophoretic mobility shift assay (EMSA) revealed binding sites for the Sp1, Ets1 and GATA transcription factors. Surprisingly, the mutation generated an additional ZNF202 binding site and this transcriptional repressor bound strongly to the mutant promoter while failing to recognize the wild-type promoter. Although the genetic causes of dystroglycanopathies are highly variable, they account for only 50% of the cases described. Our results emphasize the importance of extending the mutational screening outside the gene-coding region in dystroglycanopathy patients of unknown aetiology, because mutations in noncoding regions may be the cause of disease.
  • Calcium Sensitivity of Actomyosin Atpase

    Calcium Sensitivity of Actomyosin Atpase

    Calcium Sensitivity of Actomyosin ATPase: Its Modification by Substitution of Myosin Sulfhydryl Groups Peter Dancker Max-Planck-Institut für medizinische Forschung, Abteilung Physiologie, Heidelberg (Z. Naturforsch. 30 c, 586 — 592 [1975]; received June 30, 1975) Actomyosin ATPase, Calcium Sensitivity, Sulfhydryl Groups SH group substitution by DTNB enabled natural actomyosin to split ATP (in the presence of Mg2+) also in the absence of Ca2*, when assayed at low ionic strength. At higher KC1 concentra­ tions the ATPase activity of SH group substituted actomyosin was still Ca-dependent. Addition of unsubstituted myosin to natural actomyosin whose SH groups had been substituted increased the ATPase activity. This increase was Ca-insensitive indicating that SH group substitution of myosin in actomyosin can make the interaction of additional myosin molecules Ca-independent. In natural actomyosin Ca-insensitivity of ATPase activity was attained at a lower degree of SH group sub­ stitution when substitution was performed in the presence of EDTA. The part of ATPase activity which still remained Ca-sensitive after DTNB treatment could be activated by lower concentrations of free Ca2+ than the Ca-sensitive ATPase of untreated actomyosin. In reconstituted actomyosin the Ca-sensitivity of ATPase activity could more easily be reduced when the myosin-actin ratio was high. For demonstrating remaining Ca-sensitivity in SH group substituted reconstituted acto­ myosin more tropomyosin-troponin was needed than for sensitizing unsubstituted actomyosin to Ca2+. — The similarities between the ATPase activity of SH group substituted actomyosin on the one hand and that of actomyosin at low concentrations of ATP on the other hand suggest that SH group substitution modifies actin-myosin interaction in a similar way as does nucleotide-free myosin (rigor myosin).
  • Dystrobrevin in Nonmuscle Dystrophin-Associated Protein Complex-Like Complexes in Kidney and Liver

    Dystrobrevin in Nonmuscle Dystrophin-Associated Protein Complex-Like Complexes in Kidney and Liver

    Role of β-Dystrobrevin in Nonmuscle Dystrophin-Associated Protein Complex-Like Complexes in Kidney and Liver Nellie Y. Loh, Daniela Nebenius-Oosthuizen, Derek J. Blake, Andrew J. H. Smith and Kay E. Davies Mol. Cell. Biol. 2001, 21(21):7442. DOI: 10.1128/MCB.21.21.7442-7448.2001. Downloaded from Updated information and services can be found at: http://mcb.asm.org/content/21/21/7442 These include: http://mcb.asm.org/ REFERENCES This article cites 18 articles, 11 of which can be accessed free at: http://mcb.asm.org/content/21/21/7442#ref-list-1 CONTENT ALERTS Receive: RSS Feeds, eTOCs, free email alerts (when new articles cite this article), more» on February 25, 2014 by Cardiff Univ Information about commercial reprint orders: http://journals.asm.org/site/misc/reprints.xhtml To subscribe to to another ASM Journal go to: http://journals.asm.org/site/subscriptions/ MOLECULAR AND CELLULAR BIOLOGY, Nov. 2001, p. 7442–7448 Vol. 21, No. 21 0270-7306/01/$04.00ϩ0 DOI: 10.1128/MCB.21.21.7442–7448.2001 Copyright © 2001, American Society for Microbiology. All Rights Reserved. Role of ␤-Dystrobrevin in Nonmuscle Dystrophin-Associated Protein Complex-Like Complexes in Kidney and Liver NELLIE Y. LOH,1† DANIELA NEBENIUS-OOSTHUIZEN,2‡ DEREK J. BLAKE,1§ 2 1,3 ANDREW J. H. SMITH, AND KAY E. DAVIES * MRC Functional Genetics Unit,3 Department of Human Anatomy and Genetics,1 University of Oxford, Oxford OX1 3QX, and Centre for Genome Research, The University of Edinburgh, Edinburgh EH9 3JQ,2 United Kingdom Received 27 July 2001/Accepted 31 July 2001 Downloaded from ␤-Dystrobrevin is a dystrophin-related and -associated protein that is highly expressed in brain, kidney, and liver.
  • LARGE Expression in Different Types of Muscular Dystrophies Other Than Dystroglycanopathy Burcu Balci-Hayta1*, Beril Talim2, Gulsev Kale2 and Pervin Dincer1

    LARGE Expression in Different Types of Muscular Dystrophies Other Than Dystroglycanopathy Burcu Balci-Hayta1*, Beril Talim2, Gulsev Kale2 and Pervin Dincer1

    Balci-Hayta et al. BMC Neurology (2018) 18:207 https://doi.org/10.1186/s12883-018-1207-0 RESEARCHARTICLE Open Access LARGE expression in different types of muscular dystrophies other than dystroglycanopathy Burcu Balci-Hayta1*, Beril Talim2, Gulsev Kale2 and Pervin Dincer1 Abstract Background: Alpha-dystroglycan (αDG) is an extracellular peripheral glycoprotein that acts as a receptor for both extracellular matrix proteins containing laminin globular domains and certain arenaviruses. An important enzyme, known as Like-acetylglucosaminyltransferase (LARGE), has been shown to transfer repeating units of -glucuronic acid-β1,3-xylose-α1,3- (matriglycan) to αDG that is required for functional receptor as an extracellular matrix protein scaffold. The reduction in the amount of LARGE-dependent matriglycan result in heterogeneous forms of dystroglycanopathy that is associated with hypoglycosylation of αDG and a consequent lack of ligand-binding activity. Our aim was to investigate whether LARGE expression showed correlation with glycosylation of αDG and histopathological parameters in different types of muscular dystrophies, except for dystroglycanopathies. Methods: The expression level of LARGE and glycosylation status of αDG were examined in skeletal muscle biopsies from 26 patients with various forms of muscular dystrophy [Duchenne muscular dystrophy (DMD), Becker muscular dystrophy (BMD), sarcoglycanopathy, dysferlinopathy, calpainopathy, and merosin and collagen VI deficient congenital muscular dystrophies (CMDs)] and correlation of results with different histopathological features was investigated. Results: Despite the fact that these diseases are not caused by defects of glycosyltransferases, decreased expression of LARGE was detected in many patient samples, partly correlating with the type of muscular dystrophy. Although immunolabelling of fully glycosylated αDG with VIA4–1 was reduced in dystrophinopathy patients, no significant relationship between reduction of LARGE expression and αDG hypoglycosylation was detected.