ReviewActive killing of neurons during development and following stress: a role for p75NTR and Fas?
Introduction
It has become traditional to contrast two main scenarios for the occurrence of neuronal cell death (for a review, see [1]). On one hand, most neuronal loss during development has been considered to result from competition between neurons for limited access to neurotrophic factors: programmed cell death (PCD) is considered here as the default pathway in the absence of survival signals. On the other hand, neuronal death in response to stresses such as ischaemia, excitotoxicity or other disease processes has been considered to result from active killing.
Two principal developments in recent years have contributed to making this distinction less clear. First, stress-induced cell death has been shown in many cases to require activation of a cell death cascade, some elements of which are common to developmental and pathological cell death (for a review, see [2]). Secondly, active signalling through ‘death receptors’ has been shown to occur in immature neurons, in conditions believed to mimic naturally-occurring cell death (such as trophic deprivation). We review here recent evidence for the unexpected involvement of two members of the tumor necrosis factor receptor (TNFR) death receptor family — the p75 neurotrophin receptor (p75NTR) and Fas (CD95/Apo-1) — in neuronal death during development and in the adult, and we discuss to what extent these findings are compatible with the neurotrophic hypothesis.
Section snippets
p75NTR, the low-affinity neurotrophin receptor
Although p75NTR was the first receptor to be discovered for a neurotrophic factor, its biological role and mode of action have proved difficult to understand. In addition to its role as a co-receptor for the high-affinity neurotrophin receptors of the Trk family 3, 4, recent attention has focussed on its potential role as a death-inducer (reviewed in [5]). This role was first suggested by the fact that it is a member of the same family of transmembrane receptors as TNFR and Fas, and later
Fas (Apo-1/CD95)
Fas is a member of the same receptor family as p75NTR and has a well-studied role in programmed elimination of lymphocytes (for a review, see [21]). The concepts and reagents developed by immunologists for study of Fas and its ligand Fas-L provided an important stimulus for many new results published this year on their roles in the nervous system. We will review here only findings related to death of neurons; potential involvement of Fas in diseases such as multiple sclerosis is reviewed
Triggering neuronal death by exogenous activators of Fas
The foregoing results provide one potential answer to the question as to why neurons die in the absence of trophic factors or following stress, with Fas-L upregulation as the first step triggered by the death-inducing stimulus. Other results this year raise the possibility that Fas activation itself might in some cases be the trigger for death. Agents that cluster Fas, such as soluble Fas-L or anti-Fas antibodies, are known to trigger death of Fas-expressing thymocytes. When applied to
Downstream pathways linking Fas activation to controlled neuronal PCD
The signalling pathways used by Fas in neurons have not yet been directly studied, but we review here recent expression data concerning the major elements of known pathways (and their regulators). In cell types other than neurons, when activated by ligand the cytoplasmic domain of Fas forms a complex with the adapter protein FADD that can then trigger activation of pro-caspase-8 (Figure 1b). The interaction between FADD and pro-caspase-8 can be competed for by a cellular decoy called FLIP [41],
Conclusions
Although much still remains to be discovered, it is now clear that neurons of different classes express receptors whose activation can lead to their death. In relatively few cases thus far, activation of p75NTR or Fas has been shown to be required for neuronal death in vivo, either during development or following ischaemic stress. Although many aspects of these results deserve detailed discussion, we will focus here on just one of the questions raised for future studies: to what extent can the
Acknowledgements
We thank members of our laboratory for helpful comments. Work in the authors’ laboratory was supported by INSERM, CNRS, Association Française contre les Myopathies (AFM), Institut pour la Recherche sur la Moelle Epinière (IRME), and European Commission BIO4 contract CT960433. C Raoul is a recipient of a scholarship from the Ministère de l’Education Nationale, la Recherche et la Technologie (MENRT).
References and recommended reading
Papers of particular interest, published within the annual period of review, have been highlighted as:
• of special interest
•• of outstanding interest
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