Regeneration in the central nervous system.
Unlike neonatal axons, mammalian adult axons of the CNS do not regenerate after injury. This developmental loss of regenerative capacity, is correlated with the onset of myelination. Likewise, myelin, or myelin-associated components such as Nogo-A and myelin-associated glycoprotein (MAG) inhibit regeneration from older but not younger neurons. Identification of the molecular events responsible for this developmental loss of regenerative capacity is central to devise strategies to encourage regeneration in adults after injury. Endogenous levels of the cyclic nucleotides cAMP and cGMP have been suggested to determine the neuronal responsiveness to various axonal guidance factors. Elevating cAMP concentrations block Nogo-A or MAG induced inhibition of neurite outgrowth in older neurons, whereas suppressing cAMP levels in young neurons renders them susceptible to Nogo-A and MAG. Interestingly, elevated cAMP levels abrogated the Nogo-A and MAG mediated activation of RhoA and down regulation of Rac1 in adult neurons. In contrast, elevation of cAMP leads to the inactivation of RhoA and prevents activation of downstream effector proteins, while Rac is activated. We therefore conclude that the endogenous neuronal cAMP levels determine the neuronal responsiveness to myelin-associated neurite growth inhibitors by regulating rho GTPase activities.
Bandtlow
Christine E
CE
Division of Neurobiochemistry, Institute of Medical Chemistry and Biochemistry, Leopold-Franzens-University of Innsbruck, Fritz-Pregl-Str. 3, A-6020 Innsbruck, Austria. christine.bandtlow@uibk.ac.at
D000818:Animals; D016466:CHO Cells; D002227:Carbazoles; D002478:Cells, Cultured; D002531:Cerebellum / Q000502:physiology*; D006224:Cricetinae; D000242:Cyclic AMP / Q000037:antagonists & inhibitors / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006131:Growth Inhibitors / Q000494:pharmacology*; D007211:Indoles / Q000494:pharmacology; D009185:Myelin Proteins / Q000494:pharmacology*; D018992:Myelin-Associated Glycoprotein / Q000494:pharmacology; D009416:Nerve Regeneration / Q000187:drug effects*; D016501:Neurites / Q000187:drug effects* / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D000070798:Nogo Proteins; D011758:Pyrroles / Q000494:pharmacology; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects*; D020830:rac1 GTP-Binding Protein / Q000378:metabolism; D020742:rhoA GTP-Binding Protein / Q000378:metabolism
D002227:Carbazoles; D004791:Enzyme Inhibitors; D006131:Growth Inhibitors; D007211:Indoles; D009185:Myelin Proteins; D018992:Myelin-Associated Glycoprotein; D000070798:Nogo Proteins; D011758:Pyrroles; C000603197:Rtn4 protein, rat; C057416:KT 5720; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D020830:rac1 GTP-Binding Protein; D020742:rhoA GTP-Binding Protein