Characterization of myelin-associated glycoprotein as an inhibitor of axonal regeneration.
Item
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Title
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Characterization of myelin-associated glycoprotein as an inhibitor of axonal regeneration.
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Identifier
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AAI9908369
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identifier
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9908369
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Creator
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Tang, Song.
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Contributor
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Adviser: Marie T. Filbin
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Date
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1998
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Language
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English
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Publisher
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City University of New York.
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Subject
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Biology, Neuroscience | Biology, Molecular | Biology, Cell
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Abstract
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It is believed that inhibitors in myelin are responsible for the lack of axonal regeneration in the mammalian CNS after injury. But the precise nature of the molecules responsible for this effect is not known. Myelin-associated glycoprotein (MAG), a well characterized transmembrane glycoprotein, was shown to inhibit neurite outgrowth from all postnatal cerebellar neurons and adult dorsal root ganglion neurons. However, how MAG brings about this effect is not known. Here, we report that (1) MAG specifically binds to neurons in a sialic acid-dependent manner, (2) the soluble forms of MAG, MAG-Fc and dMAG, inhibit neurite outgrowth, and MAG is a true inhibitor of axonal regeneration, and (3) arginine 118 in the first Ig-like domain of MAG is the sialic acid binding site on MAG. Using a chimeric form of MAG, consisting of the extracellular domain of MAG fused to the Fc portion of human IgG, termed MAG-Fc, we have shown that MAG specifically binds to sialoglycoconjuagtes on neurons, and MAG-Fc specifically inhibits neurite outgrowth in sialic acid-dependent manner. In addition, we have also shown that the soluble MAG found in vivo, termed dMAG, inhibits neurite outgrowth, and the inhibition is MAG-specific and dose-dependent. Furthermore, we have found that mutation at Arg 118 in the first domain of MAG abolishes the sialic acid-dependent binding of MAG to neurons and the inhibitory effect of MAG-Fc on neurite outgrowth. However, a truncated MAG-Fc, which also binds to sialic acids on neurons, does not inhibit neurite outgrowth, and the R118-mutated MAG expressed on cell surface still inhibits neurite outgrowth. Therefore, we suggest that MAG has two recognition sites for neurons, the sialic acid binding site at R118 and a distinct inhibition site which is absent from the first three Ig-like domains.
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Type
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dissertation
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Source
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PQT Legacy CUNY.xlsx
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degree
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Ph.D.
