Transcriptional regulation of the regeneration-associated gene arginase-1 in neurons: Necessity of AP-1 in overcoming myelin inhibitors by cAMP
Monday, Nov 11, 2013, 3:00 PM - 4:00 PM
++A.09.c. Regeneration: CNS
*T. C. MA
, W. MELLADO
, A. BARCO
, S. M. MORRIS, Jr.
, R. R. RATAN
, D. E. WILLIS
Burke-Cornell Med. Res. Inst., White plains, NY;
Mol. Neurobio., Inst. de Neurociencias de Alicante, Univ. Miguel Hernandez/Consejo Superior de Investigaciones Cientificas, San Juan de Alicante, Spain;
Microbiology and Mol. Genet., Univ. of Pittsburgh, Pittsburgh, PA
Axonal regeneration in the CNS following injury is limited by many factors, including a local environment that is inhibitory to axonal growth and diminished intrinsic growth capacity of CNS neurons. Elevation of intraneuronal cAMP has been shown to overcome both intrinsic and extrinsic barriers to regeneration in the CNS. Previous studies have implicated the transcription factor CREB in mediating this effect through the de novo expression of regeneration-associated genes, including arginase-1, IL-6, and SLPI. Using arginase-1 as a member of this transcriptional program, we show that the direct regulation of arginase-1 is not mediated by CREB. Rather, using promoter deletion-reporter constructs, EMSA, and ChIP assays, we show that arginase-1 transcription is dependent on AP-1 family members. DRG neurons treated with cAMP can extend axons when grown on inhibitory myelin substrates such as myelin-associated glycoprotein (MAG). This effect is blocked by inhibiting AP-1 activity using a dominant-negative transcription factor (AFos). Additionally, expressing constitutive-active AP-1 (FosVP16) or CREB (CREBVP16) transcription factors augments the enhancement of neurite outgrowth by cAMP. Importantly, the benefit of CREBVP16 is also blocked by co-expression of AFos, suggesting that AP-1 is activated downstream of CREB. Our data suggest that AP-1 upregulates a cassette of regeneration-associated genes that is necessary for neurite outgrowth. Given that driving AP-1 or CREB transcriptional activity augments axonal growth induction by cAMP, this suggests that these pathways may be suboptimally upregulated by cAMP and that this may provide an opportunity to further enhance neuronal regeneration by targeting these transcription factors. These findings also suggest that a combination of small molecules and transcription factor delivery might be an efficient means to drive regeneration following injury.
NIH Grant R25105012
The Burke Foundation
The Dr. Miram and Sheldon G. Adelson Medical Research Foundation
New York State Spinal Cord Injury Research Board
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