Characterization of a role for cyclic AMP (cAMP) in blocking inhibition of axonal regeneration by myelin-associated glycoprotein (MAG) and myelin.

摘要

Myelin-associated glycoprotein (MAG), a well-characterized glycoprotein found in both CNS and PNS myelin, has been shown to be a potent inhibitor of axonal outgrowth in culture and in vivo. Here, we demonstrated that the inhibition of MAG/myelin on neurite outgrowth is completely blocked if neurons are exposed to neurotrophins before they encounter MAG or myelin. This priming effect is via a cAMP-dependent pathway. In addition, if neurons are exposed to MAG/myelin and neurotrophins simultaneously but in the presence of a Gi inhibitor, pertussis toxin, the inhibition is blocked without the need to prime. Therefore, we proposed a model to explain the priming effect and possible signaling mechanism involved in MAG's inhibition on axonal outgrowth.; Next, we showed that the promotion of neurite growth from younger neurons by MAG/myelin as well as the spontaneous axonal regeneration in vivo after spinal cord transection in young animals is dependent on cAMP activation. In addition, there is a decrease in endogenous cAMP levels during development, which suggests that neuronal cAMP levels dictate the developmental switch of neurons to inhibition. Furthermore, the molecular mechanism underlying the improved CNS axonal regeneration following a peripheral conditioning lesion was studied. It has been found that transection of the peripheral nerve branch of DRG neurons results in an increase in endogenous levels of cAMP, which can neutralize the effect of myelin inhibitors, and then allow injured neurons to grow through white matter. The application of cAMP directly into the neuronal cell body without any peripheral nerve lesion mimics the effect of a conditioning lesion on axonal regeneration.; Finally, the possible downstream effectors induced by cAMP were investigated. One signaling event is the up-regulation of arginase I, which in turn activates the pathway for the biosynthesis of polyamines and initiates the neuronal regenerative machinery. Blocking one step in the pathway of polyamine production, synthesis of putrescine from ornithine, with an inhibitor of ODC, abrogates cAMP-induced reversal of inhibition by MAG and myelin completely. Then, a modified model is proposed to explain the possible signal transduction mechanism involved in the neurotrophin/cAMP-induced axonal outgrowth on MAG/myelin.