Differential roles of ERK1/2 and JNK in retinal development and degeneration.
Programmed cell death is well established as a key factor in the development of the vertebrate nervous system of which the retina is a unique sensory component. However, it is of utmost importance for the survival of post-mitotic tissues such as the retina that the execution of the cell death program is kept under stringent control once development is complete. This is exemplified by the many retinal dystrophies where aberrant apoptosis results in loss of distinct cell layers in the mature retina and often culminates in blindness. In this study, we report that the extracellular signal-regulated kinase (ERK1/2) pathway plays a key role in the regulation of apoptosis during retinal development. We show that as the retina matures, the emphasis shifts towards survival and ERK1/2 is activated resulting in phosphorylation of the potent BH3-only protein Bim(EL) and a dramatic decline in Bim(EL) expression via proteasomal degradation. We find that activation of ERK1/2 also occurs in response to injury in retinal explants. However, this is a transient response and appears to be overcome by Jun N-terminal kinase activation resulting in induction of Bim(EL) mRNA and photoreceptor apoptosis. Our findings provide new insights into the intracellular pathways responsible for regulating apoptosis during neuronal development and degeneration.
Cell Development and Disease Laboratory, Department of Biochemistry, Biosciences Institute, University College Cork, Cork, Ireland. ma.donovan@ucc.ie
Maryanne
M
Donovan
Francesca
F
Doonan
Thomas G
TG
Cotter
D000818:Animals; D017209:Apoptosis / Q000502:physiology; D002478:Cells, Cultured; D005260:Female; D048031:JNK Mitogen-Activated Protein Kinases / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D019950:Mitogen-Activated Protein Kinase 1 / Q000502:physiology*; D048052:Mitogen-Activated Protein Kinase 3 / Q000502:physiology*; D012160:Retina / Q000201:enzymology* / Q000254:growth & development*; D012162:Retinal Degeneration / Q000201:enzymology* / Q000473:pathology
D048031:JNK Mitogen-Activated Protein Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3