Extracellular signal-regulated kinases 1/2 are required for adult retinal ganglion cell axon regeneration induced by fibroblast growth factor-2.
The intracellular signaling mechanisms used by neurotrophic factors to promote axon growth in the mature, injured central nervous system are not well understood. Here we investigated the signaling cascades that control fibroblast growth factor-2 (FGF-2)-mediated retinal ganglion cell (RGC) axon extension in vivo. For this purpose, a novel adeno-associated virus (AAV) was used to deliver the FGF-2 gene to RGCs, providing a sustained source of this neurotrophic factor. FGF-2 gene transfer led to an approximately ten-fold increase in the number of axons that extended past the lesion site compared with control nerves. Axon growth correlated with FGF-2-induced activation of the extracellular signal-regulated kinases 1/2 (Erk1/2), but not phosphoinositide 3-kinase or protein kinase C. Pharmacological inhibition of Erk1/2 activation resulted in an approximately 80% decrease in the number of axons that regenerated in the injured optic nerve. Our data demonstrate that the Erk1/2 pathway is an essential signaling component in FGF-2-mediated axon regeneration in the mature, injured visual system.
Sapieha
Przemyslaw S
PS
Department of Pathology and Cell Biology, Université de Montréal, Montreal, Quebec, Canada.
Hauswirth
William W
WW
Di Polo
Adriana
A
D000704:Analysis of Variance; D000818:Animals; D001369:Axons / Q000187:drug effects*; D015153:Blotting, Western / Q000379:methods; D000229:Dependovirus / Q000502:physiology; D005260:Female; D016222:Fibroblast Growth Factor 2 / Q000378:metabolism / Q000494:pharmacology*; D015870:Gene Expression / Q000502:physiology; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D019950:Mitogen-Activated Protein Kinase 1 / Q000502:physiology*; D048052:Mitogen-Activated Protein Kinase 3 / Q000502:physiology*; D020221:Optic Nerve Injuries / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012038:Regeneration / Q000187:drug effects*; D012165:Retinal Ganglion Cells / Q000166:cytology*; D013997:Time Factors
D016222:Fibroblast Growth Factor 2; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3