The Journal of Neuroscience, December 1, 2004, 24(48):10806-10815; doi:10.1523/JNEUROSCI.3532-04.2004
Previous Article | Next Article 
Development/Plasticity/Repair
Cellular Mechanisms Associated with Spontaneous and Ciliary Neurotrophic Factor-cAMP-Induced Survival and Axonal Regeneration of Adult Retinal Ganglion Cells
Kevin Park,1
Jian-Min Luo,2
Susan Hisheh,1
Alan R. Harvey,1 and
Qi Cui1,2
1School of Anatomy and Human Biology and Western Australian Institute for Medical Research, The University of Western Australia, Crawley, Perth WA 6009, Australia, and 2Laboratory for Neural Repair, Shantou University Medical College, Shantou 515031, People's Republic of China
We have shown previously that intraocular elevation of cAMP using the cAMP analog 8-(4-chlorophenylthio)-cAMP (CPT-cAMP) failed to promote axonal regeneration of axotomized adult retinal ganglion cells (RGCs) into peripheral nerve (PN) grafts but significantly potentiated ciliary neurotrophic factor (CNTF)-induced axonal regeneration. Using the PN graft model, we now examine the mechanisms underlying spontaneous and CNTF/CPT-cAMP-induced neuronal survival and axonal regrowth. We found that blockade of the cAMP pathway executor protein kinase A (PKA) using the cell-permeable inhibitor KT5720 did not affect spontaneous survival and axonal regeneration but essentially abolished the CNTF/CPT-cAMP-induced RGC survival and axonal regeneration. Blockade of CNTF signaling pathways such as phosphotidylinositol 3-kinase (PI3K)/akt by 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one (LY294002), mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) by 2-(2-diamino-3-methoxyphenyl-4H-1-benzopyran-4-one (PD98059), or Janus kinase (JAK)/signal transducer and activators of transcription (STAT3) by tyrphostin AG490 also blocked the CNTF/CPT-cAMP-dependent survival and regeneration effects. PKA activity assay and Western blots showed that KT5720, LY294002, and PD98059 almost completely inhibited PKA, PI3K/akt, and MAPK/ERK signal transduction, respectively, whereas AG490 substantially decreased JAK/STAT3 signal transduction. Intraocular injection of CPT-cAMP resulted in a small PKA-dependent increase in CNTF receptor 
mRNA expression in the retinas, an effect that may facilitate CNTF action on survival and axonal regeneration. Surprisingly, in the absence of CNTF/CPT-cAMP, LY294002, PD98059, and AG490, but not KT5720, significantly enhanced spontaneous RGC survival, suggesting differential roles of these pathways in RGC survival under different conditions. Our data suggest that CNTF/CPT-cAMP-induced RGC survival and axonal regeneration are a result of multiple pathway actions, with PKA as an essential component, but that these pathways can function in an antagonistic manner under different conditions.
Key words: ciliary neurotrophic factor; cAMP; protein kinase A; phosphotidylinositol 3-kinase; mitogen-activated protein kinase; Janus kinase
Received Sep 2, 2004;
revised October 10, 2004;
accepted October 11, 2004.
This article has been cited by other articles:
|
|
|
|
 
Y. Yin, Q. Cui, H.-y. Gilbert, Y. Yang, Z. Yang, C. Berlinicke, Z. Li, C. Zaverucha-do-Valle, H. He, V. Petkova, et al.
Oncomodulin links inflammation to optic nerve regeneration
PNAS,
November 17, 2009;
106(46):
19587 - 19592.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. R. Douglas, K. C. Morrison, S. J. Jacques, W. E. Leadbeater, A. M. Gonzalez, M. Berry, A. Logan, and Z. Ahmed
Off-target effects of epidermal growth factor receptor antagonists mediate retinal ganglion cell disinhibited axon growth
Brain,
November 1, 2009;
132(11):
3102 - 3121.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
V. Planchamp, C. Bermel, L. Tonges, T. Ostendorf, S. Kugler, J. C. Reed, P. Kermer, M. Bahr, and P. Lingor
BAG1 promotes axonal outgrowth and regeneration in vivo via Raf-1 and reduction of ROCK activity
Brain,
October 1, 2008;
131(10):
2606 - 2619.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
Q. Cui, L. Benowitz, and Y. Yin
Does CNTF mediate the effect of intraocular inflammation on optic nerve regeneration?
Brain,
June 1, 2008;
131(6):
e96 - e96.
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. Muller, T. G. Hauk, and D. Fischer
Astrocyte-derived CNTF switches mature RGCs to a regenerative state following inflammatory stimulation
Brain,
December 1, 2007;
130(12):
3308 - 3320.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
L.-P. Cen, J.-M. Luo, C.-W. Zhang, Y.-M. Fan, Y. Song, K.-F. So, N. van Rooijen, C. P. Pang, D. S. C. Lam, and Q. Cui
Chemotactic Effect of Ciliary Neurotrophic Factor on Macrophages in Retinal Ganglion Cell Survival and Axonal Regeneration
Invest. Ophthalmol. Vis. Sci.,
September 1, 2007;
48(9):
4257 - 4266.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
Z. Ahmed, G. Mazibrada, R. J. Seabright, R. G. Dent, M. Berry, and A. Logan
TACE-induced cleavage of NgR and p75NTR in dorsal root ganglion cultures disinhibits outgrowth and promotes branching of neurites in the presence of inhibitory CNS myelin
FASEB J,
September 1, 2006;
20(11):
1939 - 1941.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
V. Pernet and A. Di Polo
Synergistic action of brain-derived neurotrophic factor and lens injury promotes retinal ganglion cell survival, but leads to optic nerve dystrophy in vivo
Brain,
April 1, 2006;
129(4):
1014 - 1026.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. Yadav, A. Kalita, S. Dhillon, and K. Banerjee
JAK/STAT3 Pathway Is Involved in Survival of Neurons in Response to Insulin-like Growth Factor and Negatively Regulated by Suppressor of Cytokine Signaling-3
J. Biol. Chem.,
September 9, 2005;
280(36):
31830 - 31840.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
C.-W. Zhang, Q. Lu, S.-W. You, Y. Zhi, H. K. Yip, W. Wu, K.-F. So, and Q. Cui
CNTF and BDNF Have Similar Effects on Retinal Ganglion Cell Survival but Differential Effects on Nitric Oxide Synthase Expression Soon after Optic Nerve Injury
Invest. Ophthalmol. Vis. Sci.,
April 1, 2005;
46(4):
1497 - 1503.
[Abstract]
[Full Text]
[PDF]
|
|
|
