Expression of a dominant negative form of Daxx in vivo rescues motoneurons from Fas (CD95)-induced cell death.
Fas-induced death of motoneurons in vitro has been shown to involve two signaling cascades that act together to execute the death program: a Fas-Daxx-ASK-1-p38 kinase-nNOS branch, which controls transcriptional and post-translational events, and the second classical Fas-FADD-caspase-8 branch. To analyze the role of Daxx in the developmental motoneuron cell death, we studied Fas-dependent cell death in motoneurons from transgenic mice that overexpress a dominant-negative form of Daxx. Motoneurons purified from these transgenic mice are resistant to Fas-induced death. This protective effect is specific to Fas because ultraviolet irradiation-triggered death is not affected by the transgene. The Daxx and the FADD pathways work in parallel because only Daxx, but not FADD, is involved in the transcriptional control of neuronal nitric oxide synthase and nitric oxide production. Nevertheless, we do not observe involvement of Daxx in developmental motoneuronal cell death, as the pattern of naturally occurring programmed cell death in vivo is normal in transgenic mice overexpressing the dominant negative form of Daxx, suggesting that Daxx-independent pathways are used during development.
INSERM U. 382, Developmental Biology Institute of Marseille (CNRS-INSERM-Univ. Méditerranée-AP Marseille), Campus de Luminy-Case 907, 13288 Marseille, France.
Cedric
C
Raoul
Catherine
C
Barthelemy
Arnaud
A
Couzinet
David
D
Hancock
Brigitte
B
Pettmann
Anne-Odile
AO
Hueber
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000528:radiation effects; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002452:Cell Count / Q000379:methods; D056970:Co-Repressor Proteins; D004622:Embryo, Mammalian; D053222:Fas Ligand Protein; D005455:Fluorescent Antibody Technique / Q000379:methods; D005799:Genes, Dominant; D049452:Green Fluorescent Proteins / Q000378:metabolism; D020287:In Situ Nick-End Labeling / Q000379:methods; D007211:Indoles; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D008562:Membrane Glycoproteins; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D018832:Molecular Chaperones; D009046:Motor Neurons / Q000166:cytology*; D009419:Nerve Tissue Proteins / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000378:metabolism; D052248:Nitric Oxide Synthase Type I; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D009842:Oligopeptides; D010455:Peptides / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D013116:Spinal Cord / Q000166:cytology*; D013997:Time Factors; D019014:fas Receptor / Q000502:physiology*
D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D056970:Co-Repressor Proteins; C491473:Daxx protein, mouse; D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D007211:Indoles; D047908:Intracellular Signaling Peptides and Proteins; D008562:Membrane Glycoproteins; D018832:Molecular Chaperones; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D009842:Oligopeptides; D010455:Peptides; D012333:RNA, Messenger; D019014:fas Receptor; D049452:Green Fluorescent Proteins; C007293:DAPI; C085706:FLAG peptide; D019001:Nitric Oxide Synthase; D052248:Nitric Oxide Synthase Type I; C496321:Nos1 protein, mouse; D048031:JNK Mitogen-Activated Protein Kinases