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The Journal of Neuroscience, December 1, 2004, 24(48):10806-10815; doi:10.1523/JNEUROSCI.3532-04.2004

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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 Cui^1,2

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

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Received Sep 2, 2004; revised October 10, 2004; accepted October 11, 2004.

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