Abstract
About 50% of spinal motoneurons undergo programmed cell death (PCD) after target contact, but little is known about how this process is initiated. Embryonic motoneurons coexpress the death receptor Fas and its ligand FasL at the stage at which PCD is about to begin. In the absence of trophic factors, many motoneurons die in culture within 2 d. Most (75%) of these were saved by Fas-Fc receptor body, which blocks interactions between Fas and FasL, or by the caspase-8 inhibitor tetrapeptide IETD. Therefore, activation of Fas by endogenous FasL underlies cell death induced by trophic deprivation. In the presence of neurotrophic factors, exogenous Fas activators such as soluble FasL or anti-Fas antibodies triggered PCD of 40-50% of purified motoneurons over the following 3-5 d; this treatment led to activation of caspase-3, and was blocked by IETD. Sensitivity to Fas activation is regulated: motoneurons cultured for 3 d with neurotrophic factors became completely resistant. Levels of Fas expressed by motoneurons varied little, but FasL was upregulated in the absence of neurotrophic factors. Motoneurons resistant to Fas activation expressed high levels of FLICE-inhibitory protein (FLIP), an endogenous inhibitor of caspase-8 activation. Our results suggest that Fas can act as a driving force for motoneuron PCD, and raise the possibility that active triggering of PCD may contribute to motoneuron loss during normal development and/or in pathological situations.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Apoptosis / physiology*
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Brain-Derived Neurotrophic Factor / pharmacology
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CASP8 and FADD-Like Apoptosis Regulating Protein
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Carrier Proteins / biosynthesis
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Caspase 3
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Caspase 8
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Caspase 9
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Caspases / metabolism
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Caspases / physiology
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Cell Survival
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Cells, Cultured
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Ciliary Neurotrophic Factor / pharmacology
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Embryo, Mammalian / cytology*
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Enzyme Precursors / physiology
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Fas Ligand Protein
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Glial Cell Line-Derived Neurotrophic Factor
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Humans
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Intracellular Signaling Peptides and Proteins*
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Ligands
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Membrane Glycoproteins / antagonists & inhibitors
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Membrane Glycoproteins / biosynthesis
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Membrane Glycoproteins / physiology*
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Mice
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Motor Neurons / metabolism
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Motor Neurons / physiology*
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Nerve Growth Factors / pharmacology
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Nerve Tissue Proteins / pharmacology
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Peptides / physiology
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Rats
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fas Receptor / biosynthesis
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fas Receptor / metabolism
Substances
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Brain-Derived Neurotrophic Factor
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CASP8 and FADD-Like Apoptosis Regulating Protein
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CFLAR protein, human
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Carrier Proteins
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Cflar protein, mouse
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Ciliary Neurotrophic Factor
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Enzyme Precursors
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FASLG protein, human
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Fas Ligand Protein
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Fasl protein, mouse
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Faslg protein, rat
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GDNF protein, human
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Gdnf protein, mouse
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Gdnf protein, rat
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Glial Cell Line-Derived Neurotrophic Factor
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Intracellular Signaling Peptides and Proteins
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Ligands
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Membrane Glycoproteins
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Nerve Growth Factors
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Nerve Tissue Proteins
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Peptides
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fas Receptor
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CASP3 protein, human
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CASP8 protein, human
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CASP9 protein, human
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Casp3 protein, mouse
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Casp3 protein, rat
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Casp8 protein, mouse
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Casp8 protein, rat
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Casp9 protein, mouse
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Casp9 protein, rat
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Caspase 3
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Caspase 8
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Caspase 9
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Caspases