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Vol. 17, No. 4, 2009
Issue release date: September 2009
Neurosignals 2009;17:277–287
(DOI:10.1159/000231894)

TAM Receptor Signalling and Demyelination

Binder M.D. · Kilpatrick T.J.
Florey Neuroscience Institutes and Centre for Neuroscience, The University of Melbourne, Parkville, Vic., Australia
email Corresponding Author

Abstract

The TAM family (Tyro3, Axl and Mer) of receptor protein tyrosine kinases play pivotal roles in a number of major cellular processes: cell survival and proliferation, immunomodulation and phagocytosis. These processes are central to both the initial development and pathological course of human multiple sclerosis. All three receptors and their ligands, Gas6 (growth arrest-specific gene 6) and protein S, are expressed in the central nervous system (CNS), including in oligodendrocytes, the myelin-producing cell of the CNS. Recent studies have shown that Gas6-dependent TAM receptor signalling is an important modulator of oligodendrocyte survival and microglial phenotype both in vitro and in vivo. Multiple lines of evidence allow us to hypothesise that, during a demyelinating challenge, dysfunctional TAM receptor signalling could lead to a ‘vicious cycle’ of cell death, reduced phagocytosis and deleterious immune hyper-activation. A current challenge in this field is to expand our understanding of TAM receptor signalling from rodent models of central demyelination to human disease.


 goto top of outline Key Words

  • TAM receptor signalling
  • Demyelination
  • Tyrosine kinase
  • Multiple sclerosis

 goto top of outline Abstract

The TAM family (Tyro3, Axl and Mer) of receptor protein tyrosine kinases play pivotal roles in a number of major cellular processes: cell survival and proliferation, immunomodulation and phagocytosis. These processes are central to both the initial development and pathological course of human multiple sclerosis. All three receptors and their ligands, Gas6 (growth arrest-specific gene 6) and protein S, are expressed in the central nervous system (CNS), including in oligodendrocytes, the myelin-producing cell of the CNS. Recent studies have shown that Gas6-dependent TAM receptor signalling is an important modulator of oligodendrocyte survival and microglial phenotype both in vitro and in vivo. Multiple lines of evidence allow us to hypothesise that, during a demyelinating challenge, dysfunctional TAM receptor signalling could lead to a ‘vicious cycle’ of cell death, reduced phagocytosis and deleterious immune hyper-activation. A current challenge in this field is to expand our understanding of TAM receptor signalling from rodent models of central demyelination to human disease.

Copyright © 2009 S. Karger AG, Basel


 goto top of outline References
  1. Barnett MH, Prineas JW: Relapsing and remitting multiple sclerosis: pathology of the newly forming lesion. Ann Neurol 2004;55:458–468.
  2. Butzkueven H, Zhang JG, Soilu-Hanninen M, Hochrein H, Chionh F, Shipham KA, Emery B, Turnley AM, Petratos S, Ernst M, Bartlett PF, Kilpatrick TJ: LIF receptor signaling limits immune-mediated demyelination by enhancing oligodendrocyte survival. Nat Med 2002;8:613–619.
  3. Marriott MP, Emery B, Cate HS, Binder MD, Kemper D, Wu Q, Kolbe S, Gordon IR, Wang H, Egan G, Murray S, Butzkueven H, Kilpatrick TJ: Leukemia inhibitory factor signaling modulates both central nervous system demyelination and myelin repair. Glia 2008;56:686–698.
  4. Lai C, Lemke G: An extended family of protein-tyrosine kinase genes differentially expressed in the vertebrate nervous system. Neuron 1991;6:691–704.
  5. Janssen JW, Schulz AS, Steenvoorden AC, Schmidberger M, Strehl S, Ambros PF, Bartram CR: A novel putative tyrosine kinase receptor with oncogenic potential. Oncogene 1991;6:2113–2120.
  6. O’Bryan JP, Frye RA, Cogswell PC, Neubauer A, Kitch B, Prokop C, Espinosa R 3rd, Le Beau MM, Earp HS, Liu ET: Axl, a transforming gene isolated from primary human myeloid leukemia cells, encodes a novel receptor tyrosine kinase. Mol Cell Biol 1991;11:5016–5031.
  7. Rescigno J, Mansukhani A, Basilico C: A putative receptor tyrosine kinase with unique structural topology. Oncogene 1991;6:1909–1913.
  8. Lemke G, Rothlin CV: Immunobiology of the TAM receptors. Nat Rev Immunol 2008;8:327–336.
  9. Sasaki T, Knyazev PG, Clout NJ, Cheburkin Y, Gohring W, Ullrich A, Timpl R, Hohe-nester E: Structural basis for Gas6-Axl signalling. EMBO J 2006;25:80–87.
  10. Schneider C, King RM, Philipson L: Genes specifically expressed at growth arrest of mammalian cells. Cell 1988;54:787–793.
  11. Manfioletti G, Brancolini C, Avanzi G, Schneider C: The protein encoded by a growth arrest-specific gene (gas6) is a new member of the vitamin K-dependent proteins related to protein S, a negative coregulator in the blood coagulation cascade. Mol Cell Biol 1993;13:4976–4985.
  12. Walker FJ: Regulation of activated protein C by a new protein. A possible function for bovine protein S. J Biol Chem 1980;255:5521–5524.
  13. DiScipio RG, Davie EW: Characterization of protein S, a gamma-carboxyglutamic acid containing protein from bovine and human plasma. Biochemistry 1979;18:899–904.
  14. Nagata K, Ohashi K, Nakano T, Arita H, Zong C, Hanafusa H, Mizuno K: Identification of the product of growth arrest-specific gene 6 as a common ligand for Axl, Sky, and Mer receptor tyrosine kinases. J Biol Chem 1996;271:30022–30027.
  15. Ohashi K, Nagata K, Toshima J, Nakano T, Arita H, Tsuda H, Suzuki K, Mizuno K: Stimulation of sky receptor tyrosine kinase by the product of growth arrest-specific gene 6. J Biol Chem 1995;270:22681–22684.
  16. Stitt TN, Conn G, Gore M, Lai C, Bruno J, Radziejewski C, Mattsson K, Fisher J, Gies DR, Jones PF, et al: The anticoagulation factor protein S and its relative, Gas6, are ligands for the Tyro 3/Axl family of receptor tyrosine kinases. Cell 1995;80:661–670.
  17. Godowski PJ, Mark MR, Chen J, Sadick MD, Raab H, Hammonds RG: Reevaluation of the roles of protein S and Gas6 as ligands for the receptor tyrosine kinase Rse/Tyro 3. Cell 1995;82:355–358.
  18. Hall MO, Obin MS, Heeb MJ, Burgess BL, Abrams TA: Both protein S and Gas6 stimulate outer segment phagocytosis by cultured rat retinal pigment epithelial cells. Exp Eye Res 2005;81:581–591.
  19. Prasad D, Rothlin CV, Burrola P, Burstyn-Cohen T, Lu Q, Garcia de Frutos P, Lemke G: TAM receptor function in the retinal pigment epithelium. Mol Cell Neurosci 2006;33:96–108.
  20. Dahlback B, Lundwall A, Stenflo J: Primary structure of bovine vitamin K-dependent protein S. Proc Natl Acad Sci USA 1986;83:4199–4203.
  21. Lundwall A, Dackowski W, Cohen E, Shaffer M, Mahr A, Dahlback B, Stenflo J, Wydro R: Isolation and sequence of the cDNA for human protein S, a regulator of blood coagulation. Proc Natl Acad Sci USA 1986;83:6716–6720.
  22. Bellido-Martin L, de Frutos PG: Vitamin K-dependent actions of Gas6. Vitam Horm 2008;78:185–209.
  23. Nakano T, Ishimoto Y, Kishino J, Umeda M, Inoue K, Nagata K, Ohashi K, Mizuno K, Arita H: Cell adhesion to phosphatidylser-ine mediated by a product of growth arrest-specific gene 6. J Biol Chem 1997;272:29411–29414.
  24. Uehara H, Shacter E: Auto-oxidation and oligomerization of protein S on the apoptotic cell surface is required for Mer tyrosine kinase-mediated phagocytosis of apoptotic cells. J Immunol 2008;180:2522–2530.
  25. Mark MR, Chen J, Hammonds RG, Sadick M, Godowsk PJ: Characterization of Gas6, a member of the superfamily of G domain-containing proteins, as a ligand for Rse and Axl. J Biol Chem 1996;271:9785–9789.
  26. Tanabe K, Nagata K, Ohashi K, Nakano T, Arita H, Mizuno K: Roles of gamma-carboxylation and a sex hormone-binding globulin-like domain in receptor-binding and in biological activities of Gas6. FEBS Lett 1997;408:306–310.
  27. Pierce A, Bliesner B, Xu M, Nielsen-Preiss S, Lemke G, Tobet S, Wierman ME: Axl and Tyro3 modulate female reproduction by influencing gonadotropin-releasing hormone neuron survival and migration. Mol Endocrinol 2008;22:2481–2495.
  28. Lai C, Gore M, Lemke G: Structure, expression, and activity of Tyro 3, a neural adhesion-related receptor tyrosine kinase. Oncogene 1994;9:2567–2578.
  29. Prieto AL, Weber JL, Lai C: Expression of the receptor protein-tyrosine kinases Tyro-3, Axl, and Mer in the developing rat central nervous system. J Comp Neurol 2000;425:295–314.
  30. Mark MR, Scadden DT, Wang Z, Gu Q, Goddard A, Godowski PJ: Rse, a novel receptor-type tyrosine kinase with homology to Axl/Ufo, is expressed at high levels in the brain. J Biol Chem 1994;269:10720–10728.
  31. Binder MD, Cate HS, Prieto AL, Kemper D, Butzkueven H, Gresle MM, Cipriani T, Jokubaitis VG, Carmeliet P, Kilpatrick TJ: Gas6 deficiency increases oligodendrocyte loss and microglial activation in response to cuprizone-induced demyelination. J Neurosci 2008;28:5195–5206.
  32. Kilpatrick TJ, Ortuno D, Bucci T, Lai C, Lemke G: Rat oligodendroglia express c-met and focal adhesion kinase, protein tyrosine kinases implicated in regulating epithelial cell motility. Neurosci Lett 2000;279:5–8.
  33. Prieto AL, O’Dell S, Varnum B, Lai C: Localization and signaling of the receptor protein tyrosine kinase Tyro3 in cortical and hippocampal neurons. Neuroscience 2007;150:319–334.
  34. Prieto AL, Weber JL, Tracy S, Heeb MJ, Lai C: Gas6, a ligand for the receptor protein-tyrosine kinase Tyro-3, is widely expressed in the central nervous system. Brain Res 1999;816:646–661.
  35. Li R, Chen J, Hammonds G, Phillips H, Armanini M, Wood P, Bunge R, Godowski PJ, Sliwkowski MX, Mather JP: Identification of Gas6 as a growth factor for human Schwann cells. J Neurosci 1996;16:2012–2019.
  36. He X, Shen L, Bjartell A, Dahlback B: The gene encoding vitamin K-dependent anticoagulant protein S is expressed in multiple rabbit organs as demonstrated by northern blotting, in situ hybridization, and immu-nohistochemistry. J Histochem Cytochem 1995;43:85–96.
  37. Yanagita M, Ishii K, Ozaki H, Arai H, Nakano T, Ohashi K, Mizuno K, Kita T, Doi T: Mechanism of inhibitory effect of warfarin on mesangial cell proliferation. J Am Soc Nephrol 1999;10:2503–2509.
  38. Yin JL, Pilmore HL, Yan YQ, McCaughan GW, Bishop GA, Hambly BD, Eris JM: Expression of growth arrest-specific gene 6 and its receptors in a rat model of chronic renal transplant rejection. Transplantation 2002;73:657–660.
  39. Bellosta P, Zhang Q, Goff SP, Basilico C: Signaling through the ARK tyrosine kinase receptor protects from apoptosis in the absence of growth stimulation. Oncogene 1997;15:2387–2397.
  40. Goruppi S, Ruaro E, Schneider C: Gas6, the ligand of Axl tyrosine kinase receptor, has mitogenic and survival activities for serum starved NIH3T3 fibroblasts. Oncogene 1996;12:471–480.
  41. Valverde P, Obin MS, Taylor A: Role of Gas6/Axl signaling in lens epithelial cell proliferation and survival. Exp Eye Res 2004;78:27–37.
  42. Nakano T, Kawamoto K, Higashino K, Arita H: Prevention of growth arrest-induced cell death of vascular smooth muscle cells by a product of growth arrest-specific gene, Gas6. FEBS Lett 1996;387:78–80.
  43. Son BK, Kozaki K, Iijima K, Eto M, Kojima T, Ota H, Senda Y, Maemura K, Nakano T, Akishita M, Ouchi Y: Statins protect human aortic smooth muscle cells from inorganic phosphate-induced calcification by restoring Gas6-Axl survival pathway. Circ Res 2006;98:1024–1031.
  44. D’Arcangelo D, Gaetano C, Capogrossi MC: Acidification prevents endothelial cell apoptosis by Axl activation. Circ Res 2002;91:e4–e12.
  45. O’Donnell K, Harkes IC, Dougherty L, Wicks IP: Expression of receptor tyrosine kinase Axl and its ligand Gas6 in rheumatoid arthritis: evidence for a novel endothelial cell survival pathway. Am J Pathol 1999;154:1171–1180.
  46. Hasanbasic I, Cuerquis J, Varnum B, Blostein MD: Intracellular signaling pathways involved in Gas6-Axl-mediated survival of endothelial cells. Am J Physiol Heart Circ Physiol 2004;287:H1207–H1213.
  47. Chan MC, Mather JP, McCray G, Lee WM: Identification and regulation of receptor tyrosine kinases Rse and Mer and their ligand Gas6 in testicular somatic cells. J Androl 2000;21:291–302.
  48. Anwar A, Keating AK, Joung D, Sather S, Kim GK, Sawczyn KK, Brandao L, Henson PM, Graham DK: Mer tyrosine kinase (MerTK) promotes macrophage survival following exposure to oxidative stress. J Leukoc Biol 2009;86:73–79.
  49. Allen MP, Zeng C, Schneider K, Xiong X, Meintzer MK, Bellosta P, Basilico C, Varnum B, Heidenreich KA, Wierman ME: Growth arrest-specific gene 6 (Gas6)/adhesion related kinase (Ark) signaling promotes gonadotropin-releasing hormone neuronal survival via extracellular signal-regulated kinase (ERK) and Akt. Mol Endocrinol 1999;13:191–201.
  50. Yagami T, Ueda K, Asakura K, Sakaeda T, Nakazato H, Kuroda T, Hata S, Sakaguchi G, Itoh N, Nakano T, Kambayashi Y, Tsuzuki H: Gas6 rescues cortical neurons from amyloid beta protein-induced apoptosis. Neuropharmacology 2002;43:1289–1296.
  51. Shankar SL, O’Guin K, Cammer M, McMorris FA, Stitt TN, Basch RS, Varnum B, Shafit-Zagardo B: The growth arrest-specific gene product Gas6 promotes the survival of human oligodendrocytes via a phosphatidylinositol 3-kinase-dependent pathway. J Neurosci 2003;23:4208–4218.
  52. Shankar SL, O’Guin K, Kim M, Varnum B, Lemke G, Brosnan CF, Shafit-Zagardo B: Gas6/Axl signaling activates the phosphatidylinositol 3-kinase/Akt1 survival pathway to protect oligodendrocytes from tumor necrosis factor alpha-induced apoptosis. J Neurosci 2006;26:5638–5648.
  53. Liu D, Guo H, Griffin JH, Fernandez JA, Zlokovic BV: Protein S confers neuronal protection during ischemic/hypoxic injury in mice. Circulation 2003;107:1791–1796.
  54. Stenhoff J, Dahlback B, Hafizi S: Vitamin K-dependent Gas6 activates ERK kinase and stimulates growth of cardiac fibroblasts. Biochem Biophys Res Commun 2004;319:871–878.
  55. Benzakour O, Formstone C, Rahman S, Kanthou C, Dennehy U, Scully MF, Kakkar VV, Cooper DN: Evidence for a protein S recep-tor(s) on human vascular smooth muscle cells. Analysis of the binding characteristics and mitogenic properties of protein S on human vascular smooth muscle cells. Biochem J 1995;308:481–485.
  56. Tomobe YI, Hama H, Sakurai T, Fujimori A, Abe Y, Goto K: Anticoagulant factor protein S inhibits the proliferation of rat astrocytes after injury. Neurosci Lett 1996;214:57–60.
  57. Konishi A, Aizawa T, Mohan A, Korshunov VA, Berk BC: Hydrogen peroxide activates the Gas6-Axl pathway in vascular smooth muscle cells. J Biol Chem 2004;279:28766–28770.
  58. Demarchi F, Verardo R, Varnum B, Brancolini C, Schneider C: Gas6 anti-apoptotic signaling requires NF-kappa B activation. J Biol Chem 2001;276:31738–31744.
  59. Goruppi S, Chiaruttini C, Ruaro ME, Varnum B, Schneider C: Gas6 induces growth, beta-catenin stabilization, and T-cell factor transcriptional activation in contact-inhibited C57 mammary cells. Mol Cell Biol 2001;21:902–915.
  60. Goruppi S, Ruaro E, Varnum B, Schneider C: Requirement of phosphatidylinositol 3-kinase-dependent pathway and Src for Gas6-Axl mitogenic and survival activities in NIH 3T3 fibroblasts. Mol Cell Biol 1997;17:4442–4453.
  61. Weinger JG, Gohari P, Yan Y, Backer JM, Varnum B, Shafit-Zagardo B: In brain, Axl recruits Grb2 and the p85 regulatory subunit of PI3 kinase; in vitro mutagenesis defines the requisite binding sites for downstream Akt activation. J Neurochem 2008;106:134–146.
  62. Braunger J, Schleithoff L, Schulz AS, Kessler H, Lammers R, Ullrich A, Bartram CR, Janssen JW: Intracellular signaling of the Ufo/Axl receptor tyrosine kinase is mediated mainly by a multi-substrate docking-site. Oncogene 1997;14:2619–2631.
  63. Fridell YW, Jin Y, Quilliam LA, Burchert A, McCloskey P, Spizz G, Varnum B, Der C, Liu ET: Differential activation of the Ras/extracellular-signal-regulated protein kinase pathway is responsible for the biological consequences induced by the Axl receptor tyrosine kinase. Mol Cell Biol 1996;16:135–145.
  64. Goruppi S, Ruaro E, Varnum B, Schneider C: Gas6-mediated survival in NIH3T3 cells activates stress signalling cascade and is independent of Ras. Oncogene 1999;18:4224–4236.
  65. Lu Q, Lemke G: Homeostatic regulation of the immune system by receptor tyrosine kinases of the Tyro 3 family. Science 2001;293:306–311.
  66. Rothlin CV, Ghosh S, Zuniga EI, Oldstone MB, Lemke G: TAM receptors are pleiotropic inhibitors of the innate immune response. Cell 2007;131:1124–1136.
  67. Prinz M, Schmidt H, Mildner A, Knobeloch KP, Hanisch UK, Raasch J, Merkler D, Detje C, Gutcher I, Mages J, Lang R, Martin R, Gold R, Becher B, Brück W, Kalinke U: Distinct and nonredundant in vivo functions of IFNAR on myeloid cells limit autoimmunity in the central nervous system. Immunity 2008;28:675–686.
  68. Grommes C, Lee CY, Wilkinson BL, Jiang Q, Koenigsknecht-Talboo JL, Varnum B, Land-reth GE: Regulation of microglial phagocytosis and inflammatory gene expression by Gas6 acting on the Axl/Mer family of tyrosine kinases. J Neuroimmune Pharmacol 2008;3:130–140.
  69. Lu Q, Gore M, Zhang Q, Camenisch T, Boast S, Casagranda F, Lai C, Skinner MK, Klein R, Matsushima GK, Earp HS, Goff SP, Lemke G: Tyro-3 family receptors are essential regulators of mammalian spermatogenesis. Nature 1999;398:723–728.
  70. D’Cruz PM, Yasumura D, Weir J, Matthes MT, Abderrahim H, LaVail MM, Vollrath D: Mutation of the receptor tyrosine kinase gene Mertk in the retinal dystrophic RCS rat. Hum Mol Genet 2000;9:645–651.
  71. Gal A, Li Y, Thompson DA, Weir J, Orth U, Jacobson SG, Apfelstedt-Sylla E, Vollrath D: Mutations in MERTK, the human orthologue of the RCS rat retinal dystrophy gene, cause retinitis pigmentosa. Nat Genet 2000;26:270–271.
  72. McHenry CL, Liu Y, Feng W, Nair AR, Feathers KL, Ding X, Gal A, Vollrath D, Sieving PA, Thompson DA: MERTK arginine-844-cysteine in a patient with severe rod-cone dystrophy: loss of mutant protein function in transfected cells. Invest Ophthalmol Vis Sci 2004;45:1456–1463.
  73. Tschernutter M, Jenkins SA, Waseem NH, Saihan Z, Holder GE, Bird AC, Bhattacharya SS, Ali RR, Webster AR: Clinical characterisation of a family with retinal dystrophy caused by mutation in the Mertk gene. Br J Ophthalmol 2006;90:718–723.
  74. Seitz HM, Camenisch TD, Lemke G, Earp HS, Matsushima GK: Macrophages and dendritic cells use different Axl/Mertk/Tyro3 receptors in clearance of apoptotic cells. J Immunol 2007;178:5635–5642.
  75. Angelillo-Scherrer A, Burnier L, Lam- brechts D, Fish RJ, Tjwa M, Plaisance S, Sugamele R, DeMol M, Martinez-Soria E, Maxwell PH, Lemke G, Goff SP, Matsushi-ma GK, Earp HS, Chanson M, Collen D, Izui S, Schapira M, Conway EM, Carmeliet P: Role of Gas6 in erythropoiesis and anemia in mice. J Clin Invest 2008;118:583–596.
  76. Anderson HA, Maylock CA, Williams JA, Paweletz CP, Shu H, Shacter E: Serum-derived protein S binds to phosphatidylserine and stimulates the phagocytosis of apoptotic cells. Nat Immunol 2003;4:87–91.
  77. Wu Y, Singh S, Georgescu MM, Birge RB: A role for Mer tyrosine kinase in alphavbeta5 integrin-mediated phagocytosis of apoptotic cells. J Cell Sci 2005;118:539–553.
  78. Hall MO, Abrams TA, Burgess BL: Integrin alphavbeta5 is not required for the phagocytosis of photoreceptor outer segments by cultured retinal pigment epithelial cells. Exp Eye Res 2003;77:281–286.
  79. Hiremath MM, Saito Y, Knapp GW, Ting JP, Suzuki K, Matsushima GK: Microglial/macrophage accumulation during cuprizone- induced demyelination in C57BL/6 mice. J Neuroimmunol 1998;92:38–49.
  80. Matsushima GK, Morell P: The neurotoxicant, cuprizone, as a model to study demyelination and remyelination in the central nervous system. Brain Pathol 2001;11:107–116.
  81. Hiremath MM, Chen VS, Suzuki K, Ting JP, Matsushima GK: MHC class II exacerbates demyelination in vivo independently of T cells. J Neuroimmunol 2008;203:23–32.
  82. McMahon EJ, Suzuki K, Matsushima GK: Peripheral macrophage recruitment in cuprizone-induced CNS demyelination despite an intact blood-brain barrier. J Neuroimmunol 2002;130:32–45.
  83. Mason JL, Jones JJ, Taniike M, Morell P, Suzuki K, Matsushima GK: Mature oligodendrocyte apoptosis precedes IGF-1 production and oligodendrocyte progenitor accumulation and differentiation during demyelination/remyelination. J Neurosci Res 2000;61:251–262.
  84. Morell P, Barrett CV, Mason JL, Toews AD, Hostettler JD, Knapp GW, Matsushima GK: Gene expression in brain during cuprizone-induced demyelination and remyelination. Mol Cell Neurosci 1998;12:220–227.
  85. Hoehn HJ, Kress Y, Sohn A, Brosnan CF, Bourdon S, Shafit-Zagardo B: Axl–/– mice have delayed recovery and prolonged axonal damage following cuprizone toxicity. Brain Res 2008;1240:1–11.
  86. Kotter MR, Zhao C, van Rooijen N, Franklin RJ: Macrophage-depletion induced impairment of experimental CNS remyelination is associated with a reduced oligodendrocyte progenitor cell response and altered growth factor expression. Neurobiol Dis 2005;18:166–175.
  87. Miller RH: Contact with central nervous system myelin inhibits oligodendrocyte progenitor maturation. Dev Biol 1999;216:359–368.

 goto top of outline Author Contacts

Michele D. Binder
Florey Neuroscience Institutes and Centre for Neuroscience
The University of Melbourne
Parkville, Vic. 3010 (Australia)
Tel. +61 3 8344 0182, Fax +61 3 9348 1707, E-Mail mbinder@florey.edu.au


 goto top of outline Article Information

Received: May 14, 2009
Accepted after revision: June 7, 2009
Published online: September 30, 2009
Number of Print Pages : 11
Number of Figures : 2, Number of Tables : 0, Number of References : 87


 goto top of outline Publication Details

Neurosignals

Vol. 17, No. 4, Year 2009 (Cover Date: September 2009)

Journal Editor: Ip N.Y. (Hong Kong)
ISSN: 1424-862X (Print), eISSN: 1424-8638 (Online)

For additional information: http://www.karger.com/NSG


Copyright / Drug Dosage / Disclaimer

Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher or, in the case of photocopying, direct payment of a specified fee to the Copyright Clearance Center.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in goverment regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

Abstract

The TAM family (Tyro3, Axl and Mer) of receptor protein tyrosine kinases play pivotal roles in a number of major cellular processes: cell survival and proliferation, immunomodulation and phagocytosis. These processes are central to both the initial development and pathological course of human multiple sclerosis. All three receptors and their ligands, Gas6 (growth arrest-specific gene 6) and protein S, are expressed in the central nervous system (CNS), including in oligodendrocytes, the myelin-producing cell of the CNS. Recent studies have shown that Gas6-dependent TAM receptor signalling is an important modulator of oligodendrocyte survival and microglial phenotype both in vitro and in vivo. Multiple lines of evidence allow us to hypothesise that, during a demyelinating challenge, dysfunctional TAM receptor signalling could lead to a ‘vicious cycle’ of cell death, reduced phagocytosis and deleterious immune hyper-activation. A current challenge in this field is to expand our understanding of TAM receptor signalling from rodent models of central demyelination to human disease.



 goto top of outline Author Contacts

Michele D. Binder
Florey Neuroscience Institutes and Centre for Neuroscience
The University of Melbourne
Parkville, Vic. 3010 (Australia)
Tel. +61 3 8344 0182, Fax +61 3 9348 1707, E-Mail mbinder@florey.edu.au


 goto top of outline Article Information

Received: May 14, 2009
Accepted after revision: June 7, 2009
Published online: September 30, 2009
Number of Print Pages : 11
Number of Figures : 2, Number of Tables : 0, Number of References : 87


 goto top of outline Publication Details

Neurosignals

Vol. 17, No. 4, Year 2009 (Cover Date: September 2009)

Journal Editor: Ip N.Y. (Hong Kong)
ISSN: 1424-862X (Print), eISSN: 1424-8638 (Online)

For additional information: http://www.karger.com/NSG


Copyright / Drug Dosage

Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher or, in the case of photocopying, direct payment of a specified fee to the Copyright Clearance Center.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in goverment regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

References

  1. Barnett MH, Prineas JW: Relapsing and remitting multiple sclerosis: pathology of the newly forming lesion. Ann Neurol 2004;55:458–468.
  2. Butzkueven H, Zhang JG, Soilu-Hanninen M, Hochrein H, Chionh F, Shipham KA, Emery B, Turnley AM, Petratos S, Ernst M, Bartlett PF, Kilpatrick TJ: LIF receptor signaling limits immune-mediated demyelination by enhancing oligodendrocyte survival. Nat Med 2002;8:613–619.
  3. Marriott MP, Emery B, Cate HS, Binder MD, Kemper D, Wu Q, Kolbe S, Gordon IR, Wang H, Egan G, Murray S, Butzkueven H, Kilpatrick TJ: Leukemia inhibitory factor signaling modulates both central nervous system demyelination and myelin repair. Glia 2008;56:686–698.
  4. Lai C, Lemke G: An extended family of protein-tyrosine kinase genes differentially expressed in the vertebrate nervous system. Neuron 1991;6:691–704.
  5. Janssen JW, Schulz AS, Steenvoorden AC, Schmidberger M, Strehl S, Ambros PF, Bartram CR: A novel putative tyrosine kinase receptor with oncogenic potential. Oncogene 1991;6:2113–2120.
  6. O’Bryan JP, Frye RA, Cogswell PC, Neubauer A, Kitch B, Prokop C, Espinosa R 3rd, Le Beau MM, Earp HS, Liu ET: Axl, a transforming gene isolated from primary human myeloid leukemia cells, encodes a novel receptor tyrosine kinase. Mol Cell Biol 1991;11:5016–5031.
  7. Rescigno J, Mansukhani A, Basilico C: A putative receptor tyrosine kinase with unique structural topology. Oncogene 1991;6:1909–1913.
  8. Lemke G, Rothlin CV: Immunobiology of the TAM receptors. Nat Rev Immunol 2008;8:327–336.
  9. Sasaki T, Knyazev PG, Clout NJ, Cheburkin Y, Gohring W, Ullrich A, Timpl R, Hohe-nester E: Structural basis for Gas6-Axl signalling. EMBO J 2006;25:80–87.
  10. Schneider C, King RM, Philipson L: Genes specifically expressed at growth arrest of mammalian cells. Cell 1988;54:787–793.
  11. Manfioletti G, Brancolini C, Avanzi G, Schneider C: The protein encoded by a growth arrest-specific gene (gas6) is a new member of the vitamin K-dependent proteins related to protein S, a negative coregulator in the blood coagulation cascade. Mol Cell Biol 1993;13:4976–4985.
  12. Walker FJ: Regulation of activated protein C by a new protein. A possible function for bovine protein S. J Biol Chem 1980;255:5521–5524.
  13. DiScipio RG, Davie EW: Characterization of protein S, a gamma-carboxyglutamic acid containing protein from bovine and human plasma. Biochemistry 1979;18:899–904.
  14. Nagata K, Ohashi K, Nakano T, Arita H, Zong C, Hanafusa H, Mizuno K: Identification of the product of growth arrest-specific gene 6 as a common ligand for Axl, Sky, and Mer receptor tyrosine kinases. J Biol Chem 1996;271:30022–30027.
  15. Ohashi K, Nagata K, Toshima J, Nakano T, Arita H, Tsuda H, Suzuki K, Mizuno K: Stimulation of sky receptor tyrosine kinase by the product of growth arrest-specific gene 6. J Biol Chem 1995;270:22681–22684.
  16. Stitt TN, Conn G, Gore M, Lai C, Bruno J, Radziejewski C, Mattsson K, Fisher J, Gies DR, Jones PF, et al: The anticoagulation factor protein S and its relative, Gas6, are ligands for the Tyro 3/Axl family of receptor tyrosine kinases. Cell 1995;80:661–670.
  17. Godowski PJ, Mark MR, Chen J, Sadick MD, Raab H, Hammonds RG: Reevaluation of the roles of protein S and Gas6 as ligands for the receptor tyrosine kinase Rse/Tyro 3. Cell 1995;82:355–358.
  18. Hall MO, Obin MS, Heeb MJ, Burgess BL, Abrams TA: Both protein S and Gas6 stimulate outer segment phagocytosis by cultured rat retinal pigment epithelial cells. Exp Eye Res 2005;81:581–591.
  19. Prasad D, Rothlin CV, Burrola P, Burstyn-Cohen T, Lu Q, Garcia de Frutos P, Lemke G: TAM receptor function in the retinal pigment epithelium. Mol Cell Neurosci 2006;33:96–108.
  20. Dahlback B, Lundwall A, Stenflo J: Primary structure of bovine vitamin K-dependent protein S. Proc Natl Acad Sci USA 1986;83:4199–4203.
  21. Lundwall A, Dackowski W, Cohen E, Shaffer M, Mahr A, Dahlback B, Stenflo J, Wydro R: Isolation and sequence of the cDNA for human protein S, a regulator of blood coagulation. Proc Natl Acad Sci USA 1986;83:6716–6720.
  22. Bellido-Martin L, de Frutos PG: Vitamin K-dependent actions of Gas6. Vitam Horm 2008;78:185–209.
  23. Nakano T, Ishimoto Y, Kishino J, Umeda M, Inoue K, Nagata K, Ohashi K, Mizuno K, Arita H: Cell adhesion to phosphatidylser-ine mediated by a product of growth arrest-specific gene 6. J Biol Chem 1997;272:29411–29414.
  24. Uehara H, Shacter E: Auto-oxidation and oligomerization of protein S on the apoptotic cell surface is required for Mer tyrosine kinase-mediated phagocytosis of apoptotic cells. J Immunol 2008;180:2522–2530.
  25. Mark MR, Chen J, Hammonds RG, Sadick M, Godowsk PJ: Characterization of Gas6, a member of the superfamily of G domain-containing proteins, as a ligand for Rse and Axl. J Biol Chem 1996;271:9785–9789.
  26. Tanabe K, Nagata K, Ohashi K, Nakano T, Arita H, Mizuno K: Roles of gamma-carboxylation and a sex hormone-binding globulin-like domain in receptor-binding and in biological activities of Gas6. FEBS Lett 1997;408:306–310.
  27. Pierce A, Bliesner B, Xu M, Nielsen-Preiss S, Lemke G, Tobet S, Wierman ME: Axl and Tyro3 modulate female reproduction by influencing gonadotropin-releasing hormone neuron survival and migration. Mol Endocrinol 2008;22:2481–2495.
  28. Lai C, Gore M, Lemke G: Structure, expression, and activity of Tyro 3, a neural adhesion-related receptor tyrosine kinase. Oncogene 1994;9:2567–2578.
  29. Prieto AL, Weber JL, Lai C: Expression of the receptor protein-tyrosine kinases Tyro-3, Axl, and Mer in the developing rat central nervous system. J Comp Neurol 2000;425:295–314.
  30. Mark MR, Scadden DT, Wang Z, Gu Q, Goddard A, Godowski PJ: Rse, a novel receptor-type tyrosine kinase with homology to Axl/Ufo, is expressed at high levels in the brain. J Biol Chem 1994;269:10720–10728.
  31. Binder MD, Cate HS, Prieto AL, Kemper D, Butzkueven H, Gresle MM, Cipriani T, Jokubaitis VG, Carmeliet P, Kilpatrick TJ: Gas6 deficiency increases oligodendrocyte loss and microglial activation in response to cuprizone-induced demyelination. J Neurosci 2008;28:5195–5206.
  32. Kilpatrick TJ, Ortuno D, Bucci T, Lai C, Lemke G: Rat oligodendroglia express c-met and focal adhesion kinase, protein tyrosine kinases implicated in regulating epithelial cell motility. Neurosci Lett 2000;279:5–8.
  33. Prieto AL, O’Dell S, Varnum B, Lai C: Localization and signaling of the receptor protein tyrosine kinase Tyro3 in cortical and hippocampal neurons. Neuroscience 2007;150:319–334.
  34. Prieto AL, Weber JL, Tracy S, Heeb MJ, Lai C: Gas6, a ligand for the receptor protein-tyrosine kinase Tyro-3, is widely expressed in the central nervous system. Brain Res 1999;816:646–661.
  35. Li R, Chen J, Hammonds G, Phillips H, Armanini M, Wood P, Bunge R, Godowski PJ, Sliwkowski MX, Mather JP: Identification of Gas6 as a growth factor for human Schwann cells. J Neurosci 1996;16:2012–2019.
  36. He X, Shen L, Bjartell A, Dahlback B: The gene encoding vitamin K-dependent anticoagulant protein S is expressed in multiple rabbit organs as demonstrated by northern blotting, in situ hybridization, and immu-nohistochemistry. J Histochem Cytochem 1995;43:85–96.
  37. Yanagita M, Ishii K, Ozaki H, Arai H, Nakano T, Ohashi K, Mizuno K, Kita T, Doi T: Mechanism of inhibitory effect of warfarin on mesangial cell proliferation. J Am Soc Nephrol 1999;10:2503–2509.
  38. Yin JL, Pilmore HL, Yan YQ, McCaughan GW, Bishop GA, Hambly BD, Eris JM: Expression of growth arrest-specific gene 6 and its receptors in a rat model of chronic renal transplant rejection. Transplantation 2002;73:657–660.
  39. Bellosta P, Zhang Q, Goff SP, Basilico C: Signaling through the ARK tyrosine kinase receptor protects from apoptosis in the absence of growth stimulation. Oncogene 1997;15:2387–2397.
  40. Goruppi S, Ruaro E, Schneider C: Gas6, the ligand of Axl tyrosine kinase receptor, has mitogenic and survival activities for serum starved NIH3T3 fibroblasts. Oncogene 1996;12:471–480.
  41. Valverde P, Obin MS, Taylor A: Role of Gas6/Axl signaling in lens epithelial cell proliferation and survival. Exp Eye Res 2004;78:27–37.
  42. Nakano T, Kawamoto K, Higashino K, Arita H: Prevention of growth arrest-induced cell death of vascular smooth muscle cells by a product of growth arrest-specific gene, Gas6. FEBS Lett 1996;387:78–80.
  43. Son BK, Kozaki K, Iijima K, Eto M, Kojima T, Ota H, Senda Y, Maemura K, Nakano T, Akishita M, Ouchi Y: Statins protect human aortic smooth muscle cells from inorganic phosphate-induced calcification by restoring Gas6-Axl survival pathway. Circ Res 2006;98:1024–1031.
  44. D’Arcangelo D, Gaetano C, Capogrossi MC: Acidification prevents endothelial cell apoptosis by Axl activation. Circ Res 2002;91:e4–e12.
  45. O’Donnell K, Harkes IC, Dougherty L, Wicks IP: Expression of receptor tyrosine kinase Axl and its ligand Gas6 in rheumatoid arthritis: evidence for a novel endothelial cell survival pathway. Am J Pathol 1999;154:1171–1180.
  46. Hasanbasic I, Cuerquis J, Varnum B, Blostein MD: Intracellular signaling pathways involved in Gas6-Axl-mediated survival of endothelial cells. Am J Physiol Heart Circ Physiol 2004;287:H1207–H1213.
  47. Chan MC, Mather JP, McCray G, Lee WM: Identification and regulation of receptor tyrosine kinases Rse and Mer and their ligand Gas6 in testicular somatic cells. J Androl 2000;21:291–302.
  48. Anwar A, Keating AK, Joung D, Sather S, Kim GK, Sawczyn KK, Brandao L, Henson PM, Graham DK: Mer tyrosine kinase (MerTK) promotes macrophage survival following exposure to oxidative stress. J Leukoc Biol 2009;86:73–79.
  49. Allen MP, Zeng C, Schneider K, Xiong X, Meintzer MK, Bellosta P, Basilico C, Varnum B, Heidenreich KA, Wierman ME: Growth arrest-specific gene 6 (Gas6)/adhesion related kinase (Ark) signaling promotes gonadotropin-releasing hormone neuronal survival via extracellular signal-regulated kinase (ERK) and Akt. Mol Endocrinol 1999;13:191–201.
  50. Yagami T, Ueda K, Asakura K, Sakaeda T, Nakazato H, Kuroda T, Hata S, Sakaguchi G, Itoh N, Nakano T, Kambayashi Y, Tsuzuki H: Gas6 rescues cortical neurons from amyloid beta protein-induced apoptosis. Neuropharmacology 2002;43:1289–1296.
  51. Shankar SL, O’Guin K, Cammer M, McMorris FA, Stitt TN, Basch RS, Varnum B, Shafit-Zagardo B: The growth arrest-specific gene product Gas6 promotes the survival of human oligodendrocytes via a phosphatidylinositol 3-kinase-dependent pathway. J Neurosci 2003;23:4208–4218.
  52. Shankar SL, O’Guin K, Kim M, Varnum B, Lemke G, Brosnan CF, Shafit-Zagardo B: Gas6/Axl signaling activates the phosphatidylinositol 3-kinase/Akt1 survival pathway to protect oligodendrocytes from tumor necrosis factor alpha-induced apoptosis. J Neurosci 2006;26:5638–5648.
  53. Liu D, Guo H, Griffin JH, Fernandez JA, Zlokovic BV: Protein S confers neuronal protection during ischemic/hypoxic injury in mice. Circulation 2003;107:1791–1796.
  54. Stenhoff J, Dahlback B, Hafizi S: Vitamin K-dependent Gas6 activates ERK kinase and stimulates growth of cardiac fibroblasts. Biochem Biophys Res Commun 2004;319:871–878.
  55. Benzakour O, Formstone C, Rahman S, Kanthou C, Dennehy U, Scully MF, Kakkar VV, Cooper DN: Evidence for a protein S recep-tor(s) on human vascular smooth muscle cells. Analysis of the binding characteristics and mitogenic properties of protein S on human vascular smooth muscle cells. Biochem J 1995;308:481–485.
  56. Tomobe YI, Hama H, Sakurai T, Fujimori A, Abe Y, Goto K: Anticoagulant factor protein S inhibits the proliferation of rat astrocytes after injury. Neurosci Lett 1996;214:57–60.
  57. Konishi A, Aizawa T, Mohan A, Korshunov VA, Berk BC: Hydrogen peroxide activates the Gas6-Axl pathway in vascular smooth muscle cells. J Biol Chem 2004;279:28766–28770.
  58. Demarchi F, Verardo R, Varnum B, Brancolini C, Schneider C: Gas6 anti-apoptotic signaling requires NF-kappa B activation. J Biol Chem 2001;276:31738–31744.
  59. Goruppi S, Chiaruttini C, Ruaro ME, Varnum B, Schneider C: Gas6 induces growth, beta-catenin stabilization, and T-cell factor transcriptional activation in contact-inhibited C57 mammary cells. Mol Cell Biol 2001;21:902–915.
  60. Goruppi S, Ruaro E, Varnum B, Schneider C: Requirement of phosphatidylinositol 3-kinase-dependent pathway and Src for Gas6-Axl mitogenic and survival activities in NIH 3T3 fibroblasts. Mol Cell Biol 1997;17:4442–4453.
  61. Weinger JG, Gohari P, Yan Y, Backer JM, Varnum B, Shafit-Zagardo B: In brain, Axl recruits Grb2 and the p85 regulatory subunit of PI3 kinase; in vitro mutagenesis defines the requisite binding sites for downstream Akt activation. J Neurochem 2008;106:134–146.
  62. Braunger J, Schleithoff L, Schulz AS, Kessler H, Lammers R, Ullrich A, Bartram CR, Janssen JW: Intracellular signaling of the Ufo/Axl receptor tyrosine kinase is mediated mainly by a multi-substrate docking-site. Oncogene 1997;14:2619–2631.
  63. Fridell YW, Jin Y, Quilliam LA, Burchert A, McCloskey P, Spizz G, Varnum B, Der C, Liu ET: Differential activation of the Ras/extracellular-signal-regulated protein kinase pathway is responsible for the biological consequences induced by the Axl receptor tyrosine kinase. Mol Cell Biol 1996;16:135–145.
  64. Goruppi S, Ruaro E, Varnum B, Schneider C: Gas6-mediated survival in NIH3T3 cells activates stress signalling cascade and is independent of Ras. Oncogene 1999;18:4224–4236.
  65. Lu Q, Lemke G: Homeostatic regulation of the immune system by receptor tyrosine kinases of the Tyro 3 family. Science 2001;293:306–311.
  66. Rothlin CV, Ghosh S, Zuniga EI, Oldstone MB, Lemke G: TAM receptors are pleiotropic inhibitors of the innate immune response. Cell 2007;131:1124–1136.
  67. Prinz M, Schmidt H, Mildner A, Knobeloch KP, Hanisch UK, Raasch J, Merkler D, Detje C, Gutcher I, Mages J, Lang R, Martin R, Gold R, Becher B, Brück W, Kalinke U: Distinct and nonredundant in vivo functions of IFNAR on myeloid cells limit autoimmunity in the central nervous system. Immunity 2008;28:675–686.
  68. Grommes C, Lee CY, Wilkinson BL, Jiang Q, Koenigsknecht-Talboo JL, Varnum B, Land-reth GE: Regulation of microglial phagocytosis and inflammatory gene expression by Gas6 acting on the Axl/Mer family of tyrosine kinases. J Neuroimmune Pharmacol 2008;3:130–140.
  69. Lu Q, Gore M, Zhang Q, Camenisch T, Boast S, Casagranda F, Lai C, Skinner MK, Klein R, Matsushima GK, Earp HS, Goff SP, Lemke G: Tyro-3 family receptors are essential regulators of mammalian spermatogenesis. Nature 1999;398:723–728.
  70. D’Cruz PM, Yasumura D, Weir J, Matthes MT, Abderrahim H, LaVail MM, Vollrath D: Mutation of the receptor tyrosine kinase gene Mertk in the retinal dystrophic RCS rat. Hum Mol Genet 2000;9:645–651.
  71. Gal A, Li Y, Thompson DA, Weir J, Orth U, Jacobson SG, Apfelstedt-Sylla E, Vollrath D: Mutations in MERTK, the human orthologue of the RCS rat retinal dystrophy gene, cause retinitis pigmentosa. Nat Genet 2000;26:270–271.
  72. McHenry CL, Liu Y, Feng W, Nair AR, Feathers KL, Ding X, Gal A, Vollrath D, Sieving PA, Thompson DA: MERTK arginine-844-cysteine in a patient with severe rod-cone dystrophy: loss of mutant protein function in transfected cells. Invest Ophthalmol Vis Sci 2004;45:1456–1463.
  73. Tschernutter M, Jenkins SA, Waseem NH, Saihan Z, Holder GE, Bird AC, Bhattacharya SS, Ali RR, Webster AR: Clinical characterisation of a family with retinal dystrophy caused by mutation in the Mertk gene. Br J Ophthalmol 2006;90:718–723.
  74. Seitz HM, Camenisch TD, Lemke G, Earp HS, Matsushima GK: Macrophages and dendritic cells use different Axl/Mertk/Tyro3 receptors in clearance of apoptotic cells. J Immunol 2007;178:5635–5642.
  75. Angelillo-Scherrer A, Burnier L, Lam- brechts D, Fish RJ, Tjwa M, Plaisance S, Sugamele R, DeMol M, Martinez-Soria E, Maxwell PH, Lemke G, Goff SP, Matsushi-ma GK, Earp HS, Chanson M, Collen D, Izui S, Schapira M, Conway EM, Carmeliet P: Role of Gas6 in erythropoiesis and anemia in mice. J Clin Invest 2008;118:583–596.
  76. Anderson HA, Maylock CA, Williams JA, Paweletz CP, Shu H, Shacter E: Serum-derived protein S binds to phosphatidylserine and stimulates the phagocytosis of apoptotic cells. Nat Immunol 2003;4:87–91.
  77. Wu Y, Singh S, Georgescu MM, Birge RB: A role for Mer tyrosine kinase in alphavbeta5 integrin-mediated phagocytosis of apoptotic cells. J Cell Sci 2005;118:539–553.
  78. Hall MO, Abrams TA, Burgess BL: Integrin alphavbeta5 is not required for the phagocytosis of photoreceptor outer segments by cultured retinal pigment epithelial cells. Exp Eye Res 2003;77:281–286.
  79. Hiremath MM, Saito Y, Knapp GW, Ting JP, Suzuki K, Matsushima GK: Microglial/macrophage accumulation during cuprizone- induced demyelination in C57BL/6 mice. J Neuroimmunol 1998;92:38–49.
  80. Matsushima GK, Morell P: The neurotoxicant, cuprizone, as a model to study demyelination and remyelination in the central nervous system. Brain Pathol 2001;11:107–116.
  81. Hiremath MM, Chen VS, Suzuki K, Ting JP, Matsushima GK: MHC class II exacerbates demyelination in vivo independently of T cells. J Neuroimmunol 2008;203:23–32.
  82. McMahon EJ, Suzuki K, Matsushima GK: Peripheral macrophage recruitment in cuprizone-induced CNS demyelination despite an intact blood-brain barrier. J Neuroimmunol 2002;130:32–45.
  83. Mason JL, Jones JJ, Taniike M, Morell P, Suzuki K, Matsushima GK: Mature oligodendrocyte apoptosis precedes IGF-1 production and oligodendrocyte progenitor accumulation and differentiation during demyelination/remyelination. J Neurosci Res 2000;61:251–262.
  84. Morell P, Barrett CV, Mason JL, Toews AD, Hostettler JD, Knapp GW, Matsushima GK: Gene expression in brain during cuprizone-induced demyelination and remyelination. Mol Cell Neurosci 1998;12:220–227.
  85. Hoehn HJ, Kress Y, Sohn A, Brosnan CF, Bourdon S, Shafit-Zagardo B: Axl–/– mice have delayed recovery and prolonged axonal damage following cuprizone toxicity. Brain Res 2008;1240:1–11.
  86. Kotter MR, Zhao C, van Rooijen N, Franklin RJ: Macrophage-depletion induced impairment of experimental CNS remyelination is associated with a reduced oligodendrocyte progenitor cell response and altered growth factor expression. Neurobiol Dis 2005;18:166–175.
  87. Miller RH: Contact with central nervous system myelin inhibits oligodendrocyte progenitor maturation. Dev Biol 1999;216:359–368.