Signaling mechanisms involved in the block of MAG's inhibition of axonal regeneration.
Item
-
Title
-
Signaling mechanisms involved in the block of MAG's inhibition of axonal regeneration.
-
Identifier
-
AAI3047218
-
identifier
-
3047218
-
Creator
-
Gao, Ying.
-
Contributor
-
Adviser: Marie T. Filbin
-
Date
-
2002
-
Language
-
English
-
Publisher
-
City University of New York.
-
Subject
-
Biology, Neuroscience | Biology, Molecular
-
Abstract
-
Myelin-associated glycoprotein (MAG) is a potent inhibitor of axonal regeneration. However, prior exposure of neurons to neurotrophin (priming) blocks inhibition by MAG via a cAMP-dependent mechanism. Here we characterize the receptors and the signaling components involved in the neurotrophin/cAMP effect. First we showed that during the priming process, neurotrophins signal through the Trk receptor. Inhibition of ERK (extracellular signal-regulated kinases) by the ERK kinase (MEK) inhibitors completely abrogates both the neurotrophin and the dbcAMP effect. In addition, we demonstrate that activation of ERK by BDNF (brain-derived neurotrophic factor) down-regulates phosphodiesterase 4 (PDE4) activity and elevates CAMP levels in a MEK-dependent manner. Minimal inhibition of PDE4 by its specific inhibitor rolipram restores BDNF/cAMP's ability to overcome inhibition by MAG in the presence of the MEK inhibitor. These results suggest BDNF inhibits PDE via activated ERK to elevate cAMP and overcome myelin inhibitors of regeneration.;The CAMP response element (CRE)-binding protein (CREB) is a transcription factor induced by a variety of stimuli, including growth factors and agents that increase cAMP levels. CREB has been demonstrated to play important roles in neuronal survival and memory process. However, little is known about CREB in the process of axonal regeneration. Now we report that an inhibitor of transcription abrogates the neurotrophin/cAMP effect to overcome inhibition by MAG. We also show, in our system, that CREB is activated in response to dibutyryl CAMP and BDNF. A-CREB, a dominant-negative form of CREB that prevents wildtype CREB binding to DNA, abolishes the CRE-mediated gene expression and neurotrphin/cAMP effect on MAG. Furthermore, A-CREB prevents cAMP-dependent up-regulation of the enzyme Arg I, which has previously been shown to be essential for regulating neuronal regenerative capacity. Moreover, young dorsal root ganglion neurons that are promoted by MAG, when induced to express with A-CREB, switch their response to MAG to inhibition. These results suggest that activation of CREB, or its closely related family members, is involved in the downstream signaling by neurotrophin/cAMP to overcome MAG's inhibition.
-
Type
-
dissertation
-
Source
-
PQT Legacy CUNY.xlsx
-
degree
-
Ph.D.
