Foxo3a induces motoneuron death through the Fas pathway in cooperation with JNK.
BACKGROUND
Programmed cell death of motoneurons in the developing spinal cord is thought to be regulated through the availability of target-derived neurotrophic factors. When deprived of trophic support, embryonic spinal motoneurons in vitro over-express FasL, a ligand activating a Fas-mediated death pathway. How trophic factors regulate the expression of FasL is presently unclear, but two regulators of FasL, FOXO3a (FKHRL1) and JNK have been described to play a role in other cell types. Thus, their potential function in motoneurons was investigated in this study.


RESULTS
We show here that as a result of removal of neurotrophic factors and the consequent reduction in signalling through the PI3K/Akt pathway, Foxo3a translocates from the cytoplasm to the nucleus where it triggers cell death. Death is reduced in Fas and FasL mutant motoneurons and in the presence of JNK inhibitors indicating that a significant part of it requires activation of the Fas/FasL pathway through JNK.


CONCLUSIONS
Therefore, in motoneurons as in other cell types, FOXO transcriptional regulators provide an important link between other signalling pathways and the cell death machinery.
Barthélémy
Catherine
C
UMR 623, Developmental Biology Institute of Marseille, Centre National de la Recherche Scientifique, Institut National de la Santé et de la Recherche Médicale, Université de la Méditerranée, Marseille, France. barthelemy@ibdm.univ-mrs.fr
Henderson
Christopher E
CE
Pettmann
Brigitte
B
D000818:Animals; D017209:Apoptosis; D002478:Cells, Cultured; D053222:Fas Ligand Protein; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000032:analysis / Q000502:physiology*; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D020935:MAP Kinase Signaling System; D008562:Membrane Glycoproteins / Q000378:metabolism*; D051379:Mice; D009046:Motor Neurons / Q000166:cytology / Q000201:enzymology / Q000378:metabolism*
D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; C474033:FoxO3 protein, mouse; D008562:Membrane Glycoproteins; D048031:JNK Mitogen-Activated Protein Kinases