Mice deficient for the glycoprotein show subtle abnormalities in myelin

Montag, Dirk; Giese, K. Peter; Bartsch, Udo; Martini, Rudolf; Lang, Yolande; Blüthmann, Horst; Karthigasan, J.; Kirschner, Daniel A.; Wintergerst, E. S.; Nave, Klaus‐Armin; Zielasek, Jürgen; Toyka, Klaus V.; Lipp, Hans‐Peter; Schachner, Melitta

doi:10.1016/0896-6273(94)90472-3

Cited by 356 publications

(337 citation statements)

References 79 publications

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“…Cell culture experiments imply that MAG protein plays an important role in initiating and maintaining myelin and in axon-glial cell interaction (14). The analysis of an engineered null mutation confirmed the role of MAG in myelination, although the phenotype is surprisingly subtle (24,25). In qk v mice, MAG is expressed at a normal level, but exhibits an abnormal splicing profile (16).…”

Section: A 53-nt Sequence Is Required For Qki-5 Regulation Of Mag Exomentioning

confidence: 82%

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Function of quaking in myelination: Regulation of alternative splicing

Reed

Grabowski

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

181

214

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Proteomic diversity is frequently achieved by alternative RNAsplicing events that can be fine-tuned in tissue-specific and developmentally regulated ways. Understanding this type of genetic regulation is compelling because of the extensive complexity of alternative splicing found in the nervous system. quaking (qk), one of the classical mouse dysmyelination mutants, is defective for the expression of myelin-associated glycoprotein (MAG), and the misregulation of MAG pre-mRNA alternative splicing is implicated as a causal factor. The qk locus encodes several RNA-binding proteins with heterogeneous nuclear ribonucleoprotein K-type homology, a characteristic of several known alternative splicing regulators. Here we test the nuclear-localized qk isoform (QKI-5) for its ability to regulate alternative splicing of MAG pre-mRNA in transient coexpression assays. QKI-5 exhibits properties of a negative regulator of MAG exon 12 alternative splicing. An intronic sequence element required for the repressive function and binding of QKI-5 is also identified. Direct evidence for irregularities in alternative splicing of MAG and other myelin protein transcripts in the qk mouse is demonstrated.A lternative splicing is a powerful way to regulate gene expression at the posttranscriptional level and to generate protein diversity (1, 2). Understanding the molecular basis of such mechanisms is an urgent challenge, because the number of protein-coding genes in humans has been estimated at barely double the number in Drosophila and Caenorhabditis elegans. Between 35% and 59% of human genes are predicted to generate alternatively spliced mRNA isoforms (3).Mouse quaking (qk), also known as quaking viable (qk v ), is a classical recessive dysmyelination mutation (4). The qk locus produces a diverse set of proteins by alternative splicing (5, 6). They all contain a single heterogeneous nuclear ribonucleoprotein K homology (KH) RNA-binding domain and belong to the evolutionarily conserved signal transduction and activator of RNA (STAR) family (7,8). The first three studied in detail are constructed with the same 311-aa body, but have different carboxyl tails. QKI-5 is the only nuclear isoform and shuttles between the nucleus and cytoplasm (9, 10). The expression of QKI isoforms is developmentally regulated, with QKI-5 being highly expressed throughout the embryogenesis and neonatal stages and decreasing gradually thereafter (7, 9). In postnatal day 14 (P14) mutant mice QKI proteins are decreased exclusively in myelin-forming cells. In addition, the QKI-5 expression level in qk v brain correlates with the severity of dysmyelinating phenotype, suggesting a function of QKI-5 in myelination (9).The relationship between the decreased QKI protein in affected mice and their myelination defects is not understood. It has been shown that several myelin-specific genes are alternatively spliced, including myelin basic protein (MBP), proteolipid protein (PLP), and MAG (11-13). Some splicing events seem to be abnormal in qk v mice. The best-documented c...

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Section: A 53-nt Sequence Is Required For Qki-5 Regulation Of Mag Exomentioning

confidence: 82%

“…The abnormality of MAG alternative splicing is not likely the sole cause of the dysmyelination phenotype, because MAG knockout mice have a much less striking phenotype than qk v (24,25). Notably, several other myelin genes are also alternatively spliced (12,13).…”

Section: Resultsmentioning

confidence: 99%

Function of quaking in myelination: Regulation of alternative splicing

Reed

Grabowski

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

181

214

View full text Add to dashboard Cite

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“…Studies with knockout mice show that while MAG is not essential for myelin formation per se (Li et al, 1994), it acts to ensure myelin is appropriately produced and structured to match the specific features of the axon being enveloped (Li et al, 1994;Montag et al, 1994). The MAG extracellular domain may act as both a glue and a spacer, maintaining the glial cell membrane and the axolemma in close apposition (Li et al, 1998).…”

Section: Discussionmentioning

confidence: 99%

Cleavage of myelin associated glycoprotein by matrix metalloproteinases

Milward

Kim

Szklarczyk

et al. 2008

Journal of Neuroimmunology

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Derivative myelin associated glycoprotein (dMAG) results from proteolysis of transmembrane MAG and can inhibit axonal growth. We have tested the ability of certain matrix metalloproteinases Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. NIH Public Access

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“…For example, little axonal regeneration after CNS injury in MAG-deficient mice was noted, which may be attributed to the inherent presence of NogoA and OMgp (34,35). Similarly, in vivo application of anti-NogoA antibody, IN-1, after spinal cord injury only resulted in a small percentage of regenerating axons (21,22).…”

Section: Discussionmentioning

confidence: 99%

A Neutralizing Anti-Nogo66 Receptor Monoclonal Antibody Reverses Inhibition of Neurite Outgrowth by Central Nervous System Myelin

Walus

Rabacchi

et al. 2004

Journal of Biological Chemistry

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The Nogo66 receptor (NgR1) is a neuronal, leucinerich repeat (LRR) protein that binds three central nervous system (CNS) myelin proteins, Nogo, myelinassociated glycoprotein, and oligodendrocyte myelin glycoprotein, and mediates their inhibitory effects on neurite growth. Although the LRR domains on NgR1 are necessary for binding to the myelin proteins, the exact epitope(s) involved in ligand binding is unclear. Here we report the generation and detailed characterization of an anti-NgR1 monoclonal antibody, 7E11. The 7E11 monoclonal antibody blocks Nogo, myelin-associated glycoprotein, and oligodendrocyte myelin glycoprotein binding to NgR1 with IC 50 values of 120, 14, and 4.5 nM, respectively, and effectively promotes neurite outgrowth of P3 rat dorsal root ganglia neurons cultured on a CNS myelin substrate. Further, we have defined the molecular epitope of 7E11 to be DNAQLR located in the third LRR domain of rat NgR1. Our data demonstrate that anti-NgR1 antibodies recognizing this epitope, such as 7E11, can neutralize CNS myelin-dependent inhibition of neurite outgrowth. Thus, specific anti-NgR1 antibodies may represent a useful therapeutic approach for promoting CNS repair after injury.

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Mice deficient for the glycoprotein show subtle abnormalities in myelin

Cited by 356 publications

References 79 publications

Function of quaking in myelination: Regulation of alternative splicing

Function of quaking in myelination: Regulation of alternative splicing

Cleavage of myelin associated glycoprotein by matrix metalloproteinases

A Neutralizing Anti-Nogo66 Receptor Monoclonal Antibody Reverses Inhibition of Neurite Outgrowth by Central Nervous System Myelin

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