Fibroblast growth factor 2 applied to the optic nerve after axotomy up-regulates BDNF and TrkB in ganglion cells by activating the ERK and PKA signaling pathways.
Application of basic fibroblast growth factor (FGF-2) to the optic nerve after axotomy promotes the survival of retinal ganglion cells (RGCs) in the frog, Rana pipiens. Here we investigate the effects of FGF-2 treatment upon the synthesis of brain-derived neurotrophic factor (BDNF) and its receptor, tyrosine receptor kinase B (TrkB). Axotomy alone increased the amounts of BDNF and TrkB mRNA in RGCs after 1 week and 48 h, respectively; FGF-2 treatment to the nerve accelerated and increased this up-regulation of both. FGF-2 also increased the amounts of phosphorylated cAMP response element binding protein (pCREB) in the retina. Blocking extracellular-regulated kinase (ERK) activation with PD98059 or U0126 prevented the FGF-2-induced up-regulation of BDNF transcription but had no effect on TrkB. However, blocking protein kinase A (PKA) with H89 or Rp-8-Cl-cAMPS reduced the up-regulation of both BDNF and TrkB, and reduced pCREB. In addition, H89 inhibited ERK activation, indicating cross-talk between the pathways. Finally, axonal application of blocking antibody against the FGF receptor 1 (FGFR1) prevented the FGF-2-induced up-regulation of BDNF and TrkB. Our results suggest that FGF-2 acts on RGCs via FGFR1, activating the ERK pathway and CREB to increase BDNF synthesis, and PKA and CREB to increase TrkB synthesis.
Soto
Ileana
I
Institute of Neurobiology and Department of Anatomy, University of Puerto Rico Medical Sciences Campus, 201 Boulevard del Valle, Old San Juan, Puerto Rico 00901.
Rosenthal
Joshua J C
JJ
Blagburn
Jonathan M
JM
Blanco
Rosa E
RE
D000818:Animals; D019771:Axotomy; D015153:Blotting, Western; D019208:Brain-Derived Neurotrophic Factor / Q000096:biosynthesis*; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000502:physiology*; D018076:DNA, Complementary / Q000096:biosynthesis / Q000235:genetics; D004789:Enzyme Activation / Q000187:drug effects; D005091:Exons / Q000235:genetics; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000502:physiology*; D016222:Fibroblast Growth Factor 2 / Q000494:pharmacology*; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D020928:Mitogen-Activated Protein Kinases / Q000502:physiology; D009900:Optic Nerve / Q000187:drug effects*; D011894:Rana pipiens; D020813:Receptor, trkB / Q000096:biosynthesis*; D012165:Retinal Ganglion Cells / Q000187:drug effects / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology; D015854:Up-Regulation / Q000187:drug effects
D019208:Brain-Derived Neurotrophic Factor; D017362:Cyclic AMP Response Element-Binding Protein; D018076:DNA, Complementary; D016222:Fibroblast Growth Factor 2; D020813:Receptor, trkB; D017868:Cyclic AMP-Dependent Protein Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; D020928:Mitogen-Activated Protein Kinases