Activated CREB Is Sufficient to Overcome Inhibitors in Myelin and Promote Spinal Axon Regeneration In Vivo

Inhibitors in myelin play a major role in preventing spontaneous axonal regeneration after CNS injury. Elevation of cAMP overcomes this inhibition, in a transcription-dependent manner, through the upregulation of Arginase I ( Arg I) and increased synthesis of polyamines. Here, we show that the cAMP...

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Bibliographic Details
Published in:Neuron (Cambridge, Mass.) Mass.), 2004-11, Vol.44 (4), p.609-621
Main Authors: Gao, Ying, Deng, Kangwen, Hou, Jianwei, Bryson, J.Barney, Barco, Angel, Nikulina, Elena, Spencer, Tim, Mellado, Wilfredo, Kandel, Eric R., Filbin, Marie T.
Format: Article
Language:English
Subjects:
Animals
Arginase - metabolism
Axons - metabolism
Axons - pathology
Blotting, Western
Brain-Derived Neurotrophic Factor - metabolism
Cerebellum - metabolism
Cyclic AMP - metabolism
Cyclic AMP Response Element-Binding Protein - metabolism
Enzymes
Ganglia, Spinal - metabolism
Gene expression
Immunohistochemistry
Male
Mice
Mice, Transgenic
Myelin Sheath - metabolism
Myelin-Associated Glycoprotein - metabolism
Nerve Regeneration - physiology
Neurons
Polyamines
Proteins
Rats
Rats, Long-Evans
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Summary:Inhibitors in myelin play a major role in preventing spontaneous axonal regeneration after CNS injury. Elevation of cAMP overcomes this inhibition, in a transcription-dependent manner, through the upregulation of Arginase I ( Arg I) and increased synthesis of polyamines. Here, we show that the cAMP effect requires activation of the transcription factor cAMP response element binding protein (CREB) to overcome myelin inhibitors; a dominant-negative CREB abolishes the effect, and neurons expressing a constitutively active form of CREB are not inhibited. Activation of CREB is also required for cAMP to upregulate Arg I, and the ability of constitutively active CREB to overcome inhibition is blocked by an inhibitor of polyamine synthesis. Finally, expression of constitutively active CREB in DRG neurons is sufficient to promote regeneration of subsequently lesioned dorsal column axons. These results indicate that CREB plays a central role in overcoming myelin inhibitors and so encourages regeneration in vivo.
ISSN:0896-6273
1097-4199
DOI:10.1016/j.neuron.2004.10.030