Characterization of the role for myelin -associated glycoprotein as an inhibitor of axonal regeneration.
Item
-
Title
-
Characterization of the role for myelin -associated glycoprotein as an inhibitor of axonal regeneration.
-
Identifier
-
AAI9986377
-
identifier
-
9986377
-
Creator
-
Shen, Yingjing.
-
Contributor
-
Adviser: Marie T. Filbin
-
Date
-
2000
-
Language
-
English
-
Publisher
-
City University of New York.
-
Subject
-
Biology, Neuroscience
-
Abstract
-
It is believed that inhibitors in CNS myelin contribute substantially to the lack of regeneration in the mature mammalian CNS after injury. Here, we demonstrate that myelin-associated glycoprotein (MAG), a well-characterized myelin membrane protein, can function as a potent inhibitor for neurite regeneration. When expressed by CHO cells or by Schwann cells, MAG strongly inhibits neurite outgrowth from cerebellar neurons of all postnatal ages and DRG neurons older than postnatal day 3. In addition to its neurite extension inhibitory effect, MAG is also shown to significantly reduce neurite branching from DRG and superior cervical ganglion (SCG) neurons supported by Schwann cells. We suggest that MAG may contribute both to the inhibition of regeneration and to the limitation of collateral sprouting in myelinated regions.;It was previously shown that MAG binds to neurons in a sialic acid-dependent manner. Here we suggest that the sialic acid binding activity of MAG is distinct from its neurite growth inhibitory activity. By site-directed mutagenesis, the sialic acid binding site of MAG is mapped to arginine 118 (R118). Mutation of R118 into either alanine (R118A) or aspatic acid (R118D) completely abolishes the binding of MAG-Fc to neurons. However, when expressed by Schwann cells, R118-mutated MAG retains the ability to inhibit neurite outgrowth. Therefore, we suggest that MAG has two recognition sites for neurons, the sialic acid binding site at R118 and a distinct neurite growth inhibition site. A two-site model for the inhibition function of MAG is proposed.;The neurite growth inhibition by MAG is shown to be regulated by a neuronal cAMP-dependent activity. Elevation of neuronal cAMP levels completely abolishes the inhibition by MAG. On the other hand, addition of an antagonist of cAMP or a PKA inhibitor does not by itself induce neurite growth inhibition. Therefore, we suggest that MAG induces an inhibitory signaling pathway in neurons, which is modulated by neuronal cAMP levels, but does not directly employ a cAMP-dependent activity.
-
Type
-
dissertation
-
Source
-
PQT Legacy CUNY.xlsx
-
degree
-
Ph.D.
