Growth hormone-mediated survival of embryonic retinal ganglion cells: signaling mechanisms.
Growth hormone (GH) is found in the developing eye, where it is synthesized by retinal ganglion cells (RGCs). In this location, GH variants appear to have an autocrine or paracrine anti-apoptotic neuroprotective role, and may contribute to the regulation of the developmental waves of apoptosis that characterize RGC differentiation. Here, we investigate the intracellular signaling pathways that are activated by GH as a neuroprotective agent in cultured chick embryo RGCs. We show that GH treatment reduces the cleavage of caspase-9, and that an inhibitor of caspase-9 cleavage can abrogate the pro-apoptotic effect of GH immunoneutralization. These findings complement previous results implicating caspase-3 in GH action on these cells. We had also previously shown that Akt pathways are involved in the neuroprotection of RGCs by GH. We now extend those findings to show that these pathways involve the activation of cytosolic tyrosine kinases (Trks) and extracellular-signal-related kinases (ERKs). Therefore, although the GH receptor, unlike other neurotrophin receptors, is not itself a receptor tyrosine kinase (receptor Trk), occupation of the receptor by GH involves downstream intracellular Trk pathways. Finally, we show that the Akt and Trk pathways converge on the activation of cAMP response element binding protein (CREB) which is able to initiate transcription of pro- or anti-apoptotic genes. These results indicate that the action of GH in the neuroprotection of embryonic RGCs involves pathways that are common to other neurotrophins, and that GH can be considered to be an authentic growth and differentiation factor in the development of the embryonic retina.
Sanders
Esmond J
EJ
Department of Physiology, University of Alberta, 87Av and 114St, Edmonton, Alta., Canada T6G 1Y6. esmond.sanders@ualberta.ca <esmond.sanders@ualberta.ca>
Parker
Eve
E
Harvey
Steve
S
D000818:Animals; D015153:Blotting, Western; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism; D002070:Butadienes / Q000494:pharmacology; D053453:Caspase 9 / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D002642:Chick Embryo; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D013006:Growth Hormone / Q000494:pharmacology*; D007150:Immunohistochemistry; D009570:Nitriles / Q000494:pharmacology; D010766:Phosphorylation; D020812:Receptor, trkC / Q000037:antagonists & inhibitors / Q000378:metabolism; D012160:Retina / Q000196:embryology*; D012165:Retinal Ganglion Cells / Q000187:drug effects*; D015398:Signal Transduction / Q000187:drug effects*
D019208:Brain-Derived Neurotrophic Factor; D002070:Butadienes; D017362:Cyclic AMP Response Element-Binding Protein; D004791:Enzyme Inhibitors; D009570:Nitriles; C113580:U 0126; D013006:Growth Hormone; D020812:Receptor, trkC; D048049:Extracellular Signal-Regulated MAP Kinases; D053453:Caspase 9