MAG - Revision history

Carole Weaver: /* Glycogene microarray */

2011-03-30T23:36:29Z

Glycogene microarray

Carole Weaver at 18:59, 20 September 2010

2010-09-20T18:59:13Z

Carole Weaver: /* Carbohydrate ligands */

2010-09-20T18:53:18Z

Carbohydrate ligands

Carole Weaver at 18:52, 20 September 2010

2010-09-20T18:52:27Z

Carole Weaver: /* Progress toward understanding this GBP paradigm */

2010-08-06T17:31:33Z

Progress toward understanding this GBP paradigm

Anna Crie: /* Biological roles of GBP-ligand interaction */

2010-07-20T02:11:02Z

Biological roles of GBP-ligand interaction

Anna Crie: /* Biological roles of GBP-ligand interaction */

2010-07-20T02:10:37Z

Biological roles of GBP-ligand interaction

Anna Crie: /* Biosynthesis of ligands */

2010-07-20T02:09:44Z

Biosynthesis of ligands

Anna Crie: /* Cellular expression of GBP and ligands */

2010-07-20T02:09:28Z

Cellular expression of GBP and ligands

Anna Crie: /* Cellular expression of GBP and ligands */

2010-07-20T02:08:29Z

Cellular expression of GBP and ligands

@@ Line 78: / Line 78: @@
 <br>
 === Glycogene microarray ===
 === Knockout mouse lines ===
 The CFG has [https://www.functionalglycomics.org/glycomics/publicdata/phenotyping.jsp phenotyped] the MAG-deficient mouse.

@@ Line 40: / Line 40: @@
 === Cellular expression of GBP and ligands ===
-MAG (Siglec-4) is expressed exclusively on myelin, which is produced by oligodendrocytes (the myelinating cells of the central nervous system) and Schwann cells (the myelinating cells of the peripheral nervous system). In both central and peripheral nervous systems, MAG is enriched on the innermost wrap of myelin, directly apposing the axon surface.<ref name="quarles2007">Quarles RH. Myelin-associated glycoprotein (MAG): past, present and beyond. J Neurochem. 100, 1431-1448 (2007).</ref><br>
+MAG (Siglec-4) is expressed exclusively on myelin, which is produced by oligodendrocytes (the myelinating cells of the central nervous system) and Schwann cells (the myelinating cells of the peripheral nervous system). In both central and peripheral nervous systems, MAG is enriched on the innermost wrap of myelin, directly apposing the axon surface.<ref name="quarles2007">Quarles RH. Myelin-associated glycoprotein (MAG): past, present and beyond. J Neurochem. 100, 1431-1448 (2007).</ref><br> MAG recognizes as ligands sialoside sequences found on gangliosides that are abundant in axonal membranes<ref name="Schnaar 2009"/>.
 === Biosynthesis of ligands ===

@@ Line 37: / Line 37: @@
 [[File:Sia3Gal3(Sia6)GalNAc_small.png]]
-Mouse knockout experiments have implicated MAG-binding brain gangliosides GD1a and/or GT1b as MAG ligands (see below).<br>
+Mouse knockout experiments have implicated MAG-binding brain gangliosides GD1a and/or GT1b as MAG ligands (see "Biosynthesis of Ligands" below).<br>
 === Cellular expression of GBP and ligands ===

@@ Line 37: / Line 37: @@
 [[File:Sia3Gal3(Sia6)GalNAc_small.png]]
-<br>
+Mouse knockout experiments have implicated MAG-binding brain gangliosides GD1a and/or GT1b as MAG ligands (see below).<br>
 === Cellular expression of GBP and ligands ===

@@ Line 5: / Line 5: @@
 == Progress toward understanding this GBP paradigm ==
+This section documents what is currently known about MAG, its carbohydrate ligand(s), and how they interact to mediate cell communication. Further information can be found in the GBP Molecule Pages for [http://www.functionalglycomics.org/glycomics/molecule/jsp/viewGbpMolecule.jsp?gbpId=cbp_hum_Itlect_271&sideMenu=no human] and [http://www.functionalglycomics.org/glycomics/molecule/jsp/viewGbpMolecule.jsp?gbpId=cbp_mou_Itlect_196&sideMenu=no mouse] MAG (a.k.a. Siglec-4a) in the CFG database.
 === Carbohydrate ligands ===
 The glycan specificity of Siglec-4 has been investigated using resialylated erythrocytes<ref>Kelm, S. et al. Sialoadhesin, myelin-associated glycoprotein and CD22 define a new family of sialic acid-dependent adhesion molecules of the immunoglobulin superfamily. Curr Biol. 4, 965-972 (1994)</ref>, gangliosides<ref>Collins, B. E., Kiso, M., Hasegawa, A., Tropak, M. B., Roder, J. C., Crocker, P. R., Schnaar, R. L. Binding specificities of the sialoadhesin family of I-type lectins. Sialic acid linkage and substructure requirements for binding of myelin-associated glycoprotein, Schwann cell myelin protein, and sialoadhesin. J Biol Chem. 272, 16889-16895 (1997)</ref><ref>Collins, B. E., Yang, L. J., Mukhopadhyay, G., Filbin, M. T., Kiso, M., Hasegawa, A., Schnaar, R.L. Sialic acid specificity of myelin-associated glycoprotein binding. J Biol Chem. 272, 1248-1255 (1997)</ref>, and inhibition assays with oligosaccharides<ref name="strenge1998">Strenge, K., Schauer, R., Bovin, N., Hasegawa, A., Ishida, H., Kiso, M., Kelm, S. Glycan specificity of myelin-associated glycoprotein and sialoadhesin deduced from interactions with synthetic oligosaccharides. Eur J Biochem. 258, 677-685 (1998)</ref><ref>Blixt, O., Collins, B. E., van den Nieuwenhof, I. M., Crocker,  P. R., Paulson, J. C. Sialoside specificity of the siglec family assessed using novel multivalent probes: identification of potent inhibitors of myelin-associated glycoprotein. J Biol Chem. 278, 31007-31019 (2003)</ref>.

@@ Line 62: / Line 62: @@
 glycoprotein differently regulate oligodendrocyte maturation and myelin formation. J Neurosci. 16, 7435-44 (2008).</ref><ref name="susuki2007">Susuki K., Baba H., Tohyama K., Kanai K., Kuwabara S., Hirata K., Furukawa K., Furukawa K., Rasband M.N., Yuki N. Gangliosides contribute to stability of paranodal junctions and ion channel clusters in myelinated nerve fibers. Glia 55, 746-757. 2007.</ref>
 <br>
-. Cytoskeletal organization: <i>B4galnt1</i>-null, <i>Mag</i>-null and double-null mice have similarly reduced neurofilament spacing and reduced axon diameter.<ref name="pan2005"/></p><p></p>
+. Cytoskeletal organization: <i>B4galnt1</i>-null, <i>Mag</i>-null and double-null mice have similarly reduced neurofilament spacing and reduced axon diameter.<ref name="pan2005"/>
 <br>
 . Axon protection: MAG-mediated protection of axons from toxic insults is diminished in <i>B4galnt1</i>-null mice or after treatment of axons with sialidase.<ref name="nguyen2009">Nguyen T., Mehta N.R., Conant K., Kim K.J., Jones M., Calabresi P.A., Melli G., Hoke A., Schnaar R.L., Ming G.L., Song H., Keswani S.C., Griffin J.W. Axonal protective effects of the myelin-associated glycoprotein. J Neurosci. 21, 630-637 (2009).</ref><ref name="mehta2010">Mehta N.R., Nguyen T., Bullen J.W., Griffin J.W., Schnaar R.L. Myelin-associated glycoprotein (MAG) protects neurons from acute toxicity using a ganglioside-dependent mechanism. ACS Chem Neurosci. 1, 215-222, 2010.</ref>

@@ Line 53: / Line 53: @@
 === Biological roles of GBP-ligand interaction ===
 MAG is expressed on the innermost myelin membrane wrap, directly apposed to the axon surface. Although it is not required for myelination, MAG enhances long-term axon survival, helps structure myelin gaps (nodes of Ranvier) essential for rapid nerve conduction, regulates the axon cytoskeleton and protects axons from acute toxic insults. In addition to its role in axon-myelin stabilization, MAG inhibits axon regeneration after injury; MAG on residual myelin membranes at injury sites actively signals axons to halt elongation. Whether MAG's stabilizing effects and its inhibition of axon regeneration are part of the same signaling system is under investigation.
-<br>MAG is expressed on the innermost myelin membrane wrap, directly apposed to the axon surface. Although it is not required for myelination, MAG enhances long-term axon survival, helps structure myelin gaps (nodes of Ranvier) essential for rapid nerve conduction, regulates the axon cytoskeleton and protects axons from acute toxic insults. In addition to its role in axon-myelin stabilization, MAG inhibits axon regeneration after injury; MAG on residual myelin membranes at injury sites actively signals axons to halt elongation. Whether MAG's stabilizing effects and its inhibition of axon regeneration are part of the same signaling system is under investigation.
+<br>
 MAG has multiple receptors on the axon surface, including gangliosides GD1a/GT1b, the GPI-anchored Nogo receptors (NgR1 and NgR2), and transmembrane proteins PirB and β-integrin. Some of these interactions involve MAG's glycan binding capability, while others may not. The following biological roles of MAG have been experimentally linked to its glycan binding activity using genetic, biochemical, and/or pharmacological criteria:
-<br><br>
+<br>
 . Long term axon stabilization: <i>B4galnt1</i>-null mice, which lack the termini of complex gangliosides, display the same progressive axon degeneration phenotype as <i>Mag</i>-null mice. Double null mice (<i>B4galnt1</i>, <i>Mag</i>) are similar. <ref name="pan2005"/>
-<br><br>
+<br>
 . Nodes of Ranvier: <i>B4galnt1</i>-null and <i>Mag</i>-null mice have similar deficits in the structures of Nodes of Ranvier<ref name="pernet2008">Pernet V., Joly S., Christ F., Dimou L., Schwab M.E. Nogo-A and myelin-associated
 glycoprotein differently regulate oligodendrocyte maturation and myelin formation. J Neurosci. 16, 7435-44 (2008).</ref><ref name="susuki2007">Susuki K., Baba H., Tohyama K., Kanai K., Kuwabara S., Hirata K., Furukawa K., Furukawa K., Rasband M.N., Yuki N. Gangliosides contribute to stability of paranodal junctions and ion channel clusters in myelinated nerve fibers. Glia 55, 746-757. 2007.</ref>
-<br><br>
+<br>
 . Cytoskeletal organization: <i>B4galnt1</i>-null, <i>Mag</i>-null and double-null mice have similarly reduced neurofilament spacing and reduced axon diameter.<ref name="pan2005"/></p><p></p>
-<br><br>
+<br>
 . Axon protection: MAG-mediated protection of axons from toxic insults is diminished in <i>B4galnt1</i>-null mice or after treatment of axons with sialidase.<ref name="nguyen2009">Nguyen T., Mehta N.R., Conant K., Kim K.J., Jones M., Calabresi P.A., Melli G., Hoke A., Schnaar R.L., Ming G.L., Song H., Keswani S.C., Griffin J.W. Axonal protective effects of the myelin-associated glycoprotein. J Neurosci. 21, 630-637 (2009).</ref><ref name="mehta2010">Mehta N.R., Nguyen T., Bullen J.W., Griffin J.W., Schnaar R.L. Myelin-associated glycoprotein (MAG) protects neurons from acute toxicity using a ganglioside-dependent mechanism. ACS Chem Neurosci. 1, 215-222, 2010.</ref>
-<br><br>
+<br>
 . Regulating axon regeneration: MAG-mediated inhibition of axon regeneration is diminished in <i>B4galnt1</i>-null mice, after treatment with sialidase, or by addition of MAG-binding soluble glycans.<ref name="vyas2002">Vyas A.A., Patel H.V., Fromholt S.E., Heffer-Lauc M., Vyas K.A., Dang J., Schachner M., Schnaar R.L. Gangliosides are functional nerve cell ligands for myelin-associated glycoprotein (MAG), an inhibitor of nerve regeneration. Proc Natl Acad Sci U S A 99, 8412-8417, 2002.</ref><ref name="vyas2005"/>
-<br><br>
+<br>
 MAG signaling is bidirectional,<ref name="quarles2007"/> into the myelinating cells and into myelin-ensheathed axons. Signaling into myelinating cells may involve tyrosine phosphorylation of the MAG intracellular domain downstream of ligand engagement,<ref name="umemori1994"/><ref name="jaramillo1994"/> whereas signals into the axon are likely to involve activation of the small non-receptor GTPase RhoA.<ref name="yiu2006">Yiu G., He Z. Glial inhibition of CNS axon regeneration. Nat. Rev. Neurosci. 7, 617–627, 2006.</ref>
 <br>

@@ Line 43: / Line 43: @@
 === Biosynthesis of ligands ===
-<br>Mice null for the ganglioside-specific N-acetylgalactosaminyltransferase gene <i>B4galnt1</i> (GM2/GD2 synthase) have similar nervous system phenotypic deficits as MAG-null mice (see "Biological roles of GBP-ligand interaction" below). These data implicate MAG-binding brain gangliosides GD1a and/or GT1b as MAG ligands.<ref name="pan2005">Pan, B., Fromholt, S.E., Hess, E.J., Crawford, T.O., Griffin, J.W., Sheikh, K.A., Schnaar, R.L. Myelin-associated glycoprotein and gangliosides mediate axon-myelin stability: Neuropathology and behavioral deficits in single- and double-null mice. Exp. Neurol. 195, 208-217 (2005)</ref>.<br>
+Mice null for the ganglioside-specific N-acetylgalactosaminyltransferase gene <i>B4galnt1</i> (GM2/GD2 synthase) have similar nervous system phenotypic deficits as MAG-null mice (see "Biological roles of GBP-ligand interaction" below). These data implicate MAG-binding brain gangliosides GD1a and/or GT1b as MAG ligands.<ref name="pan2005">Pan, B., Fromholt, S.E., Hess, E.J., Crawford, T.O., Griffin, J.W., Sheikh, K.A., Schnaar, R.L. Myelin-associated glycoprotein and gangliosides mediate axon-myelin stability: Neuropathology and behavioral deficits in single- and double-null mice. Exp. Neurol. 195, 208-217 (2005)</ref>.<br>
 === Structure ===