scispace - formally typeset
Search or ask a question
Journal Article•DOI•

Major glycan structure underlying expression of the Lewis X epitope in the developing brain is O-mannose-linked glycans on phosphacan/RPTPβ.

Shohei Yaji1, Hiroshi Manya, Naoki Nakagawa1, Hiromu Takematsu1, Tamao Endo, Reiji Kannagi2, Toru Yoshihara3, Masahide Asano, Shogo Oka1 •
Kyoto University1, Aichi Medical University2, Kanazawa University3
01 Apr 2015-Glycobiology (Oxford University Press)-Vol. 25, Iss: 4, pp 376-385
TL;DR: The results revealed the importance of O-mannosylated glycan chains in the presentation of functional glycan epitopes in the brain.
Abstract: Glycosylation is a major protein modification. Although proteins are glycosylated/further modulated by several glycosyltransferases during trafficking from the endoplasmic reticulum to the Golgi apparatus, a certain glycan epitope has only been detected on a limited number of proteins. Of these glycan epitopes, Lewis X is highly expressed in the early stage of a developing brain and plays important roles in cell-cell interaction. The Lewis X epitope is comprised of a trisaccharide (Galβ1-4 (Fucα1-3) GlcNAc), and a key enzyme for the expression of this epitope is α1,3-fucosyltransferase 9. However, the scaffolding glycan structure responsible for the formation of the Lewis X epitope as well as its major carrier protein has not been fully characterized in the nervous system. Here we showed that the Lewis X epitope was mainly expressed on phosphacan/receptor protein tyrosine phosphatase β (RPTPβ) in the developing mouse brain. Expression of the Lewis X epitope was markedly reduced in β1,4-galactosyltransferase 2 (β4GalT2) gene-deficient mice, which indicated that β4GalT2 is a major galactosyltransferase required for the Lewis X epitope. We also showed that the Lewis X epitope almost disappeared due to the knockout of protein O-mannose β1,2-N-acetylglucosaminyltransferase 1, an N-acetylglucosaminyltransferase essential for the synthesis of O-mannosylated glycans, which indicated that the O-mannosylated glycan is responsible for presenting the Lewis X epitope. Since O-mannosylated glycans on phosphacan/RPTPβ could also present human natural killer-1, another glycan epitope specifically expressed in the nervous system, our results revealed the importance of O-mannosylated glycan chains in the presentation of functional glycan epitopes in the brain.

Content maybe subject to copyright    Report

Citations
More filters
Journal Article•DOI•
Eukaryotic protein glycosylation: a primer for histochemists and cell biologists.

[...]

Anthony P. Corfield1•
Bristol Royal Infirmary1
01 Feb 2017-Histochemistry and Cell Biology
TL;DR: Following this educational survey, examples where known biological function is related to the glycan structures carried by proteins are given and mucins and their glycosylation patterns are considered as instructive proof-of-principle case.
Abstract: Proteins undergo co- and posttranslational modifications, and their glycosylation is the most frequent and structurally variegated type. Histochemically, the detection of glycan presence has first been performed by stains. The availability of carbohydrate-specific tools (lectins, monoclonal antibodies) has revolutionized glycophenotyping, allowing monitoring of distinct structures. The different types of protein glycosylation in Eukaryotes are described. Following this educational survey, examples where known biological function is related to the glycan structures carried by proteins are given. In particular, mucins and their glycosylation patterns are considered as instructive proof-of-principle case. The tissue and cellular location of glycoprotein biosynthesis and metabolism is reviewed, with attention to new findings in goblet cells. Finally, protein glycosylation in disease is documented, with selected examples, where aberrant glycan expression impacts on normal function to let disease pathology become manifest. The histological applications adopted in these studies are emphasized throughout the text.

108 citations

Cites background from "Major glycan structure underlying e..."

  • ...…Yanagisawa) coding Galβ1,4(Fucα1,3)GlcNAcβ1- (Yu and Yanagisawa 2006), while O-mannosylation is also a significant feature of α-dystroglycan in the nervous system, where it mediates cell-extracellular matrix contact (Hennet 2009; Panin and Wells 2014; Praissman and Wells 2014; Yaji et al. 2015)....

    [...]

  • ...Neural stem cells express CD15 (Yu and Yanagisawa) coding Galβ1,4(Fucα1,3)GlcNAcβ1- (Yu and Yanagisawa 2006), while O-mannosylation is also a significant feature of α-dystroglycan in the nervous system, where it mediates cell-extracellular matrix contact (Hennet 2009; Panin and Wells 2014; Praissman and Wells 2014; Yaji et al. 2015)....

    [...]

Journal Article•DOI•
Recent advancements in understanding mammalian O-mannosylation.

[...]

M. Osman Sheikh1, Stephanie M. Halmo1, Lance Wells1•
University of Georgia1
01 Sep 2017-Glycobiology
TL;DR: This review will focus on recent discoveries delineating the various enzymes, structures and functions associated with O-mannose-initiated glycoproteins, and discusses the evolution of this pathway.
Abstract: The post-translational glycosylation of select proteins by O-linked mannose (O-mannose or O-man) is a conserved modification from yeast to humans and has been shown to be necessary for proper development and growth. The most well studied O-mannosylated mammalian protein is α-dystroglycan (α-DG). Hypoglycosylation of α-DG results in varying severities of congenital muscular dystrophies, cancer progression and metastasis, and inhibited entry and infection of certain arenaviruses. Defects in the gene products responsible for post-translational modification of α-DG, primarily glycosyltransferases, are the basis for these diseases. The multitude of clinical phenotypes resulting from defective O-mannosylation highlights the biomedical significance of this unique modification. Elucidation of the various O-mannose biosynthetic pathways is imperative to understanding a broad range of human diseases and for the development of novel therapeutics. In this review, we will focus on recent discoveries delineating the various enzymes, structures and functions associated with O-mannose-initiated glycoproteins. Additionally, we discuss current gaps in our knowledge of mammalian O-mannosylation, discuss the evolution of this pathway, and illustrate the utility and limitations of model systems to study functions of O-mannosylation.

72 citations

Journal Article•DOI•
GDP-l-fucose synthase is a CD4+ T cell–specific autoantigen in DRB3*02:02 patients with multiple sclerosis

[...]

Raquel Planas1, Radleigh G. Santos2, Paula Tomas-Ojer1, Carolina Cruciani1, Andreas Lutterotti1, Wolfgang Faigle1, Nicole Schaeren-Wiemers3, Carmen Espejo4, Herena Eixarch4, Clemencia Pinilla2, Roland Martin1, Mireia Sospedra1 •
University of Zurich1, Torrey Pines Institute for Molecular Studies2, University Hospital of Basel3, Autonomous University of Barcelona4
10 Oct 2018-Science Translational Medicine
TL;DR: GDP-l-fucose synthase is an autoantigen recognized by cerebrospinal fluid–infiltrating CD4+ T cells from HLA-DRB3*–positive patients with multiple sclerosis, and the possible role of this antigen as an inducer or driver of pathogenic autoimmune responses in multiple sclerosis is suggested.
Abstract: Multiple sclerosis is an immune-mediated autoimmune disease of the central nervous system that develops in genetically susceptible individuals and likely requires environmental triggers. The autoantigens and molecular mimics triggering the autoimmune response in multiple sclerosis remain incompletely understood. By using a brain-infiltrating CD4 + T cell clone that is clonally expanded in multiple sclerosis brain lesions and a systematic approach for the identification of its target antigens, positional scanning peptide libraries in combination with biometrical analysis, we have identified guanosine diphosphate (GDP)–l-fucose synthase as an autoantigen that is recognized by cerebrospinal fluid–infiltrating CD4 + T cells from HLA-DRB3*–positive patients. Significant associations were found between reactivity to GDP-l-fucose synthase peptides and DRB3*02:02 expression, along with reactivity against an immunodominant myelin basic protein peptide. These results, coupled with the cross-recognition of homologous peptides from gut microbiota, suggest a possible role of this antigen as an inducer or driver of pathogenic autoimmune responses in multiple sclerosis.

66 citations

Journal Article•DOI•
Low-density lipoprotein receptor-related protein 1 is a novel modulator of radial glia stem cell proliferation, survival, and differentiation.

[...]

Dina Safina1, Frederik Schlitt1, Ramona Romeo1, Thorsten Pflanzner2, Claus U. Pietrzik2, Vasanthy Narayanaswami3, Frank Edenhofer, Andreas Faissner1 •
Ruhr University Bochum1, University of Mainz2, California State University, Long Beach3
01 Aug 2016-Glia
TL;DR: It is shown that LeX‐glycosylated LRP1 is also expressed in the stem cell compartment of the developing spinal cord and has broader functions in the developing CNS, suggesting that LRP 1 facilitates NSPCs differentiation via interaction with apolipoprotein E (ApoE).
Abstract: The LDL family of receptors and its member low-density lipoprotein receptor-related protein 1 (LRP1) have classically been associated with a modulation of lipoprotein metabolism. Current studies, however, indicate diverse functions for this receptor in various aspects of cellular activities, including cell proliferation, migration, differentiation, and survival. LRP1 is essential for normal neuronal function in the adult CNS, whereas the role of LRP1 in development remained unclear. Previously, we have observed an upregulation of LewisX (LeX) glycosylated LRP1 in the stem cells of the developing cortex and demonstrated its importance for oligodendrocyte differentiation. In the current study, we show that LeX-glycosylated LRP1 is also expressed in the stem cell compartment of the developing spinal cord and has broader functions in the developing CNS. We have investigated the basic properties of LRP1 conditional knockout on the neural stem/progenitor cells (NSPCs) from the cortex and the spinal cord, created by means of Cre-loxp-mediated recombination in vitro. The functional status of LRP1-deficient cells has been studied using proliferation, differentiation, and apoptosis assays. LRP1 deficient NSPCs from both CNS regions demonstrated altered differentiation profiles. Their differentiation capacity toward oligodendrocyte progenitor cells (OPCs), mature oligodendrocytes and neurons was reduced. In contrast, astrocyte differentiation was promoted. Moreover, LRP1 deletion had a negative effect on NSPCs proliferation and survival. Our observations suggest that LRP1 facilitates NSPCs differentiation via interaction with apolipoprotein E (ApoE). Upon ApoE4 stimulation wild type NSPCs generated more oligodendrocytes, but LRP1 knockout cells showed no response. The effect of ApoE seems to be independent of cholesterol uptake, but is rather mediated by downstream MAPK and Akt activation. GLIA 2016 GLIA 2016;64:1363-1380.

46 citations

Cites background from "Major glycan structure underlying e..."

  • ...We confirmed already known LeX presenting proteins such as phosphacan, tenascin-C, and L1-CAM (Garwood et al., 1999; Hennen et al., 2013; Streit et al., 1990; Yaji et al., 2015)....

    [...]

Journal Article•DOI•
Glycosylation with ribitol-phosphate in mammals: New insights into the O-mannosyl glycan.

[...]

Hiroshi Manya, Tamao Endo
01 Oct 2017-Biochimica et Biophysica Acta
TL;DR: O-mannosyl glycan has a novel, unique structure that is important for the maintenance of brain and muscle functions that has opened up a new field in glycoscience.

45 citations

References
More filters
Journal Article•DOI•
β-1,4-Galactosyltransferase III Enhances Invasive Phenotypes Via β1-Integrin and Predicts Poor Prognosis in Neuroblastoma

[...]

Hsiu-Hao Chang1, Chia-Hua Chen1, Chih-Hsing Chou1, Yung-Feng Liao2, Miao-Juei Huang1, Ya-Hsin Chen1, Wei-Jen Wang1, John Huang1, Ji-Shiang Hung1, Wan-Ling Ho3, Yung-Ming Jeng1, Mei-Ieng Che1, Hsinyu Lee1, Meng-Yao Lu1, Yung-Li Yang1, Shiann-Tarng Jou1, Dong-Tsamn Lin1, Kai-Hsin Lin1, Wen-Ming Hsu1, Min-Chuan Huang1 •
National Taiwan University1, Academia Sinica2, Fu Jen Catholic University3
01 Apr 2013-Clinical Cancer Research
TL;DR: The findings suggest that B4GALT3 predicts an unfavorable prognosis for NB and may regulate invasive phenotypes through modulating glycosylation, degradation, and signaling of β1-integrin in NB cells.
Abstract: Purpose: Neuroblastoma (NB) is a neural crest-derived tumor that commonly occurs in childhood. β-1,4-Galactosyltransferase III (B4GALT3) is highly expressed in human fetal brain and is responsible for the generation of poly- N -acetyllactosamine, which plays a critical role in tumor progression. We therefore investigated the expression and role of B4GALT3 in NB. Experimental Design: We examined B4GALT3 expression in tumor specimens from 101 NB patients by immunohistochemistry and analyzed the correlation between B4GALT3 expression and clinicopathologic factors or survival. The functional role of B4GALT3 expression was investigated by overexpression or knockdown of B4GALT3 in NB cells for in vitro and in vivo studies. Results: We found that B4GALT3 expression correlated with advanced clinical stages ( P = 0.040), unfavorable Shimada histology ( P P Conclusions: Our findings suggest that B4GALT3 predicts an unfavorable prognosis for NB and may regulate invasive phenotypes through modulating glycosylation, degradation, and signaling of β1-integrin in NB cells. Clin Cancer Res; 19(7); 1705–16. ©2013 AACR .

38 citations

"Major glycan structure underlying e..." refers background in this paper

  • ...Of those, β4GalT1-4 could be involved in the biosynthesis of polyLacNAc (Ujita et al. 1998; Ujita et al. 1999; Chang et al. 2013)....

    [...]

Journal Article•DOI•
Structurally Distinct LewisX Glycans Distinguish Subpopulations of Neural Stem/Progenitor Cells

[...]

Eva Hennen1, Tim Czopka, Andreas Faissner•
Ruhr University Bochum1
06 May 2011-Journal of Biological Chemistry
TL;DR: The novel monoclonal antibody clone 5750 is introduced and it is shown that it specifically labels cell surfaces of neural stem and progenitor cells and provides insights into the complexity of cell surface glycosylation.

38 citations

"Major glycan structure underlying e..." refers background in this paper

  • ...Previous studies showed that Lewis X epitope levels were developmentally regulated at O ndokuz M ayis U niversity on N ovem ber 12, 2014 http://glycob.oxfordjournals.org/ D ow nloaded from during brain development (Gocht et al. 1996; Hennen et al. 2011)....

    [...]

  • ...be presented on the N-glycan of tenascin-C (Hennen et al. 2011) and low density lipoprotein receptor-related protein-1 (LRP-1) (Hennen et al....

    [...]

  • ...…such as tenascin-C (over 250 kDa), L1 cell adhesion molecule (L1-CAM, approximately 140 kDa), and LRP-1 (515 kDa α-subunit and 85 kDa β-subunit) (Hennen et al. 2011; Hennen et al. 2013), and also on O-mannosylated glycans of CD24 (approximately 30 kDa) or α-DG (100-120 kDa) (Smalheiser et al.…...

    [...]

  • ...Lewis X was previously reported to be presented on the N-glycan of tenascin-C (Hennen et al. 2011) and low density lipoprotein receptor-related protein-1 (LRP-1) (Hennen et al. 2013)....

    [...]

  • ...Tenascin-C was also analyzed because it could bear the Lewis X epitope and had the high molecular weight (over 250 kDa) (Hennen et al. 2011)....

    [...]

Journal Article•DOI•
Pax6 Controls the Expression of Lewis x Epitope in the Embryonic Forebrain by Regulating α1,3-Fucosyltransferase IX Expression

[...]

Yasushi Shimoda1, Youichi Tajima1, Taka Osanai1, Asao Katsume1, Michinori Kohara1, Takashi Kudo2, Hisashi Narimatsu2, Noriko Takashima, Yasushi Ishii, Shun Nakamura, Noriko Osumi, Yutaka Sanai1 •
Institute of Medical Science1, Soka University of America2
18 Jan 2002-Journal of Biological Chemistry
TL;DR: Results strongly suggest that Pax6 controls Lewis x expression in the embryonic brain by regulating FucT-IX gene expression.

37 citations

"Major glycan structure underlying e..." refers background in this paper

  • ...…250 kDa), L1 cell adhesion molecule (L1-CAM, approximately 140 kDa), and LRP-1 (515 kDa α-subunit and 85 kDa β-subunit) (Hennen et al. 2011; Hennen et al. 2013), and also on O-mannosylated glycans of CD24 (approximately 30 kDa) or α-DG (100-120 kDa) (Smalheiser et al. 1998; Bleckmann et al. 2009)....

    [...]

Journal Article•
CD15-containing glycoconjugates in the central nervous system.

[...]

A Gocht, G Struckhoff, J Lhler
01 Oct 1996-Histology and Histopathology
TL;DR: Immunohistochemical studies revealed a widespread distribution of CD15 in several epithelial non-neural tissues as well as in the CNS, which points to specialized functions of astroglial subpopulations of neurons in the mature mammalian brain.
Abstract: CD15-containing glycoconjugates have a common trisaccharide residue, 3-fucosyl-N-acetyllactosamine, which can be recognized by a panel of monoclonal antibodies. Immunohistochemical studies revealed a widespread distribution of CD15 in several epithelial non-neural tissues as well as in the CNS. In the mature mammalian brain CD15-containing glycolipids and glycoproteins are constantly present in astrocytes, whereas oligodendrocytes and particular subpopulations of neurons are variably immunostained. CD15 immunoreactive astrocytes are spatially distributed in some brain regions, which points to specialized functions of astroglial subpopulations. The expression of CD15 follows a timely ordered pattern during the development of glial cells and neurons of certain brain areas, such as the human and rat cerebellum and the mouse visual system. During morphogenesis, CD15 may exert either growth-promoting or growth-repulsive activities to guide cell migration. In CNS lesions altered expression patterns of CD15 may occur. For example, in human gliomas the staining intensity for CD15 inversely correlates with the grade of malignancy. In degenerative brain diseases reactive astrocytes may reveal an increased labelling intensity on their cell surface as well as an abnormal cytosolic accumulation of the epitope. The functional significance of CD15 in the CNS is not exactly known yet. The carbohydrate could be involved in cellular adhesion and/or as receptor molecule in signal transduction pathways, as has recently been demonstrated for leukocyte-platelet or leukocyte-endothelial cell interactions.

35 citations

"Major glycan structure underlying e..." refers background in this paper

  • ...Previous studies showed that Lewis X epitope levels were developmentally regulated at O ndokuz M ayis U niversity on N ovem ber 12, 2014 http://glycob.oxfordjournals.org/ D ow nloaded from during brain development (Gocht et al. 1996; Hennen et al. 2011)....

    [...]

  • ...Developmental changes in expression of the Lewis X epitope in the mouse brain The presence of the Lewis X epitope was previously shown to be developmentally regulated in the developing rodent brain (Gocht et al 1996)....

    [...]

  • ...It is known to be both temporally and spatially regulated in the nervous system (Gocht et al 1996); thus, this epitope is a useful maker for neural stem and progenitor cells (Hennen et al. 2011)....

    [...]

Journal Article•DOI•
A LewisX Glycoprotein Screen Identifies the Low Density Lipoprotein Receptor-related Protein 1 (LRP1) as a Modulator of Oligodendrogenesis in Mice

[...]

Eva Hennen, Dina Safina, Ute Haussmann1, Philipp Wörsdörfer2, Frank Edenhofer2, Ansgar Poetsch1, Andreas Faissner •
Ruhr University Bochum1, University of Bonn2
07 Jun 2013-Journal of Biological Chemistry
TL;DR: First evidence that LRP1 is necessary for the differentiation of neural stem cells toward oligodendrocytes is provided, however, this function is independent of LeX glycosylation.

34 citations

"Major glycan structure underlying e..." refers background in this paper

  • ...Lewis X was previously reported to be presented on the N-glycan of tenascin-C (Hennen et al. 2011) and low density lipoprotein receptor-related protein-1 (LRP-1) (Hennen et al. 2013)....

    [...]

  • ...…(over 250 kDa), L1 cell adhesion molecule (L1-CAM, approximately 140 kDa), and LRP-1 (515 kDa α-subunit and 85 kDa β-subunit) (Hennen et al. 2011; Hennen et al. 2013), and also on O-mannosylated glycans of CD24 (approximately 30 kDa) or α-DG (100-120 kDa) (Smalheiser et al. 1998; Bleckmann et…...

    [...]

  • ...The Lewis X epitope in the nervous system was shown to be expressed on N-glycans of several glycoproteins such as tenascin-C (over 250 kDa), L1 cell adhesion molecule (L1-CAM, approximately 140 kDa), and LRP-1 (515 kDa α-subunit and 85 kDa β-subunit) (Hennen et al. 2011; Hennen et al. 2013), and also on O-mannosylated glycans of CD24 (approximately 30 kDa) or α-DG (100-120 kDa) (Smalheiser et al. 1998; Bleckmann et al. 2009)....

    [...]

Related Papers (5)
A Unique β1,3-Galactosyltransferase Is Indispensable for the Biosynthesis of N-Glycans Containing Lewis a Structures in Arabidopsis thaliana

[...]

01 Jul 2007-The Plant Cell
Richard Strasser, Jayakumar Singh Bondili, Ulrike Vavra, Jennifer Schoberer, Barbara Svoboda, Josef Glössl, Renaud Léonard, Johannes Stadlmann, Friedrich Altmann, Herta Steinkellner, Lukas Mach 
Loss of branched O-mannosyl glycans in astrocytes accelerates remyelination.

[...]

12 Jun 2013-The Journal of Neuroscience
Kenji Kanekiyo, Kei-ichiro Inamori, Shinobu Kitazume, Keiko Sato, Jun Maeda, Makoto Higuchi, Yasuhiko Kizuka, Hiroaki Korekane, Ichiro Matsuo, Koichi Honke, Naoyuki Taniguchi 
The Lecticans of Mammalian Brain Perineural Net Are O-Mannosylated

[...]

01 Mar 2013-Journal of Proteome Research
Sandra Pacharra, Franz-Georg Hanisch, Martina Mühlenhoff, Andreas Faissner, Uwe Rauch, Isabelle Breloy 
Mining the O-mannose glycoproteome reveals cadherins as major O-mannosylated glycoproteins

[...]

24 Dec 2013-Proceedings of the National Academy of Sciences of the United States of America
Malene Bech Vester-Christensen, Adnan Halim, Hiren J. Joshi, Catharina Steentoft, Eric P. Bennett, Steven B. Levery, Sergey Y. Vakhrushev, Henrik Clausen 
Bisecting GlcNAc Is a General Suppressor of Terminal Modification of N-glycan.

[...]

02 Aug 2019-Molecular & Cellular Proteomics
Miyako Nakano, Sushil Kumar Mishra, Yuko Tokoro, Keiko Sato, Kazuki Nakajima, Yoshiki Yamaguchi, Naoyuki Taniguchi, Yasuhiko Kizuka