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• W2022101852 abstract "One of the most striking features of the rapidly developing field of the study of programmed cell death (PCD) has been the relative universality of many of the mechanisms uncovered and, indeed, of the very existence of molecular apoptotic programs. The possibility of using information from one system to understand death in other, very different cells will undoubtedly continue to be a major impetus for discovery. However, the final purpose and detailed implications of PCD may vary considerably from system to system. Careful analysis of the cell death process in each population is therefore required if the normal biology of apoptosis is to be understood in depth. This is particularly true in the developing nervous system, where many different cell types undergo PCD at different stages. Indeed, early work by V. Hamburger and R. Levi-Montalcini on naturally occurring and lesion-induced cell death of developing neurons laid the foundations for the subsequent explosion of the study of apoptosis in general. Even they, however, may not have suspected at the time the extent to which such concepts would permeate different aspects of developmental neurobiology. Many striking illustrations of this were provided by presentations at a recent workshop organized at the Juan March Institute in Madrid by R. W. Oppenheim (Wake Forest University), E. M. Johnson (Washington University), and J. X. Comella (University of Lleida) on “Programmed Cell Death in the Developing Nervous System.” The results presented demonstrate that not only do different neural cells die for different reasons and by different mechanisms, but that in a given cell, the precise mechanism of PCD may vary as a function of the death-inducing stimulus. I have organized this meeting review along the lines of the temporal sequence of events that take place in a cell undergoing PCD. The first phase, often referred to as the “triggering” of cell death, groups together a series of influences that may instigate the death process in vivo, but which are less irrevocable or immediate than the firing of a pistol. I have therefore referred to these collectively as “life on the edge.” A cell in this situation has subsequently to take the decision to die or to survive (“Will she, won't he?”), and then to initiate the complex series of molecular and morphological changes involved in cell death and disposal of the remains (“Getting on with the job”). The distinction between these three phases is not as clear in many vertebrate neural cells as in the nematode, in particular because a given effector may act at more than one stage in the process. However, they continue to provide a useful framework for comparing results from different systems. In summarizing the many new results presented during the three days of the workshop, I will adopt the convention of citing only the presenting author, even when unpublished work from other laboratories was discussed. Several of the earliest experiments underlying our understanding of cell death were aimed at defining the trophic dependence of a given cell on interactions with its cellular partners. Although the first of these were performed over 90 years ago (Oppenheim; P. G. H. Clarke, University of Lausanne), experimental ablation of cells or tissues in vivo continues to provide much new information, especially since classical microsurgery techniques (Oppenheim) can now be combined with the more cell-specific methods of pharmacological (J. Calderò, University of Lleida; Clarke) or genetic (K. White, Massachusetts General Hospital) cell removal. However, biological systems do not react passively to such insults, and this can lead to problems of interpretation. A nice example of this is provided by one of the classical ablation models (Oppenheim). Following limb-bud removal in the early chick embryo, there is massive motor neuron loss in the spinal cord, but only a 50% loss of sensory neurons, suggesting that the latter may survive independently of their target tissue. In fact, this turns out to be due at least in part to an adaptive reaction of the sensory neurons themselves. In the absence of limb, they project ectopically to the tail bud, where they presumably find alternative trophic support. When the tail bud is removed as well, then sensory neuron numbers are further reduced (Oppenheim). Even where trophic support is important, it may not be the only factor involved in regulating neuron numbers during the period of naturally occurring cell death. Only male zebra finches sing, and this correlates with sex-related differences in several nuclei implicated in song behavior that result from increased PCD in females (E. J. Nordeen, University of Rochester). Section of afferent pathways from the lateral magnocellular nucleus and the high vocal center leads in both sexes to increased PCD in the robust nucleus of the anterior neostriatum (RA; 1Burek M.J. Nordeen K.W. Nordeen E.J. Initial sex differences in neuron growth and survival within an avian song nucleus develop in the absence of afferent input.J. Neurobiol. 1995; 27: 85-96Crossref PubMed Scopus (20) Google Scholar). However, the sex-related differences in neuron numbers are retained, suggesting that hormonal influences play an important role in committing some neurons to PCD. It is possible that these influences may be mediated by sex differences in gliogenesis in the RA nucleus that are apparent before the onset of sexually dimorphic PCD (17Nordeen E.J. Nordeen K.W. Sex differences among non-neuronal cells precedes sexually dimorphic neuron growth and survival in an avian song control nucleus.J. Neurobiol. 1996; 30: 531-542Crossref PubMed Scopus (19) Google Scholar). Identification of the trophic factors that mediate the survival-promoting effects of one cell population on another has been the focus of intensive effort for many years now. As a result, not only are the physiologically relevant factors now quite numerous, but they turn out to belong to a number of different gene families (neurotrophins, cytokines, transforming growth factor βs, etc.) that was completely unsuspected 10 years ago (7Henderson C.E. Role of neurotrophic factors in neuronal development.Curr. Opin. Neurobiol. 1996; 6: 64-70Crossref PubMed Scopus (248) Google Scholar). Nevertheless, there was a general consensus at the meeting that, in spite of the plethora of available candidates, more trophic factors must remain to be discovered. For example, motor neuron death resulting from early limb-bud ablation can be significantly reduced by the administration of muscle extract in ovo (Oppenheim). In contrast, most of the factors that can reduce naturally occurring motor neuron death are without effect on target-deprived motor neurons; only glial cell line–derived neurotrophic factor (GDNF) has a modest protective effect. In another system, a significant fraction of postnatal retinal ganglion (RG) neurons can be kept alive in culture for long periods by combinations of brain-derived neurotrophic factor (BDNF), ciliary neurotrophic factor (CNTF), and insulin (B. Barres, Stanford University). However, embryonic RG neurons do not respond to any combination of the known factors tested. Their survival requires the presence of tectal conditioned medium (in combination with BDNF); it is therefore likely that this conditioned medium contains novel trophic factors (12Meyer-Franke A. Kaplan M.R. Pfrieger F.W. Barres B.A. Characterization of the signaling interactions that promote the survival and growth of developing retinal ganglion cells in culture.Neuron. 1995; 15: 805-819Abstract Full Text PDF PubMed Scopus (716) Google Scholar). Knockout mice for the components of the CNTF receptor complex lose about 40% of their motoneurons during embryogenesis (2DeChiara T.M. Vejsada R. Poueymirou W.T. Acheson A. Suri C. Conover J.C. Friedman B. McClain J. Pan L. Stahl N. Ip N.Y. Kato A. Yancopoulos G.D. Mice lacking the CNTF receptor, unlike mice lacking CNTF, exhibit profound motor neuron deficits at birth.Cell. 1995; 83: 313-322Abstract Full Text PDF PubMed Scopus (339) Google Scholar, 10Li M. Sendtner M. Smith A. Essential function of LIF receptor in motor neurons.Nature. 1995; 378: 724-727Crossref PubMed Scopus (270) Google Scholar), whereas double null mutants for CNTF and leukemia inhibitory factor (LIF) do not show motoneuron loss over the same period (21Sendtner M. Götz R. Holtmann B. Escary J.-L. Masu Y. Carroll P. Wolf E. Brem G. Brûlet P. Thoenen H. Cryptic physiological trophic support of motoneurons by LIF revealed by double gene targeting of CNTF and LIF.Curr. Biol. 1996; 6: 686-694Abstract Full Text Full Text PDF PubMed Scopus (142) Google Scholar), suggesting that another ligand must signal through the CNTF receptor on embryonic motoneurons. A potential candidate for this role was cardiotrophin-1 (CT-1), a novel member of the interleukin-6 cytokine family. However, although CT-1 is indeed secreted by embryonic muscle and is a potent motor neuron survival factor in vivo and in vitro (C. E. Henderson, Developmental Biology Institute of Marseille), it does not seem to signal through the CNTF receptor α subunit (19Pennica D. Arce V.A. Swanson T.A. Vejsada R. Pollock R.A. Armanini M. Dudley K. Phillips H.S. Rosenthal A. Kato A.C. Henderson C.E. Cardiotrophin-1, a cytokine present in embryonic muscle, supports long-term survival of spinal motoneurons.Neuron. 1996; 17: 63-74Abstract Full Text Full Text PDF PubMed Scopus (182) Google Scholar). The most probable conclusion is that another member of this cytokine family, capable of signaling through the CNTF receptor complex, remains to be discovered. It is perhaps of significance that all the examples cited concern neurons of the central nervous system. It is becoming evident that the clear-cut trophic dependence of some peripheral systems is not found in central neurons, which seem to survive best of all in the presence of combinations of trophic factors (Barres; Henderson), particularly when they are depolarized (Barres). It is fortunate in many respects that the situation is simpler for peripheral neurons. Without the rapid, reproducible, and complete neuronal death seen in cultures of sympathetic neurons deprived of nerve growth factor (NGF) (Figure 1), it is hard to imagine that a workshop such as this could ever have taken place, since these cells provide a powerful model for identification of molecular apoptotic pathways (Johnson; A. M. Davies, University of St. Andrews; L. A. Greene, Columbia University; R. Sadoul, Geneva Biomedical Research Institute; A. M. Tolkovsky, University of Cambridge). Neuronal death may not only result from a lack of trophic support, but also through the action of death-inducing molecules that have an early effect on the death process. Indeed, the two causes of death may be inextricably linked. Two death-inducing molecules, p75LNGFR and Reaper (members of the “cellular Addams family;” D. E. Bredesen, La Jolla Cancer Research Foundation; White), share with the tumor necrosis factor (TNF) receptor a conserved sequence in their cytoplasmic domain called the “death domain.” However, the similarities between these death domains should not conceal their differences: distinct amino acid residues seem to be essential for different members of the family (White). p75, the low affinity neurotrophin receptor, can transduce signals leading to apoptosis in some cells, though there is not general agreement on whether proapoptotic signals are transduced by the occupied or the unoccupied receptor, or perhaps by both as a function of the cell type involved (Bredesen). The reaper (rpr) gene in Drosophila is found adjacent to genes for other killer proteins such as head involution defective (hid) and grim; deletion of this portion of the genome leads to an absence of PCD in Drosophila embryos and an increase in the number of cells in the central nervous system (5Grether M.E. Abrams J.M. Agapite J. White K. Steller H. The head involution defective gene of Drosophila melanogaster functions in programmed cell death.Genes Dev. 1995; 9: 1694-1708Crossref PubMed Scopus (572) Google Scholar). Although the rpr and hid genes do not share extensive homology, they seem to act in parallel, as each alone is sufficient to trigger cell death by a pathway involving proteases of the ced-3/ICE class (25White K. Tahaoglu E. Steller H. Cell killing by Drosophila reaper.Science. 1996; 271: 805-807Crossref PubMed Scopus (329) Google Scholar). The action of these genes is required for cell death induced by other means, as for instance in the crumbs mutation, characterized by abnormal separation of epithelial cells and their subsequent death. In double mutants for crumbs and the rpr/hid/grim deletion, the morphology is not corrected, but there is no PCD (White). Expression of rpr can be triggered by a variety of signals. One example of these is X-irradiation, which induces rpr and leads to ectopic apoptosis. In this process, Rpr is not the only effector, as even in rpr-deficient mutants, apoptotic figures and engulfment of cells can be observed following irradiation. In neither of the above situations is it known how rpr comes to be up-regulated in the cells that will die. However, in the ecdysone-dependent neuronal cell death that occurs in the later stages of metamorphosis in insects, it is now known that rpr is expressed by the neurons that will die from the moment at which they can no longer be rescued by hormone injection (J. W. Truman, University of Washington). In this model, ecdysone down-regulates the levels of rpr transcripts. The downstream functions of rpr are still poorly understood. Some strong suppressor mutations have been identified and can in many cases prevent the action of both rpr and hid. These genes have not yet been characterized, but some of them may be members of a family of ICE-related genes (White). A novel death-inducing molecule has been identified by screening for monoclonal antibodies that induce apoptosis in cells to which they bind (Bredesen). One such antibody, NAIM-1, when added to cultures of cortical neurons induces activation of the ICE family proteases and causes massive cell death that is inhibited by BCL2 expression. The corresponding antigen has now been purified. Surprisingly, it is a glycosphingolipid, called DING-1 (Bredesen). Its chemical nature makes it a “portable” death-inducing molecule. When added to cells, it is incorporated into membranes and will only induce death in the presence of the correct antibody. There is a precedent for such a role for lipids from outside the nervous system: another glycolipid, Gb3/CD77, can induce apoptosis in Burkitt's lymphoma cells when bound by a bacterial toxin. It is tempting to speculate (Bredesen) that the anti-glycolipid antibodies reported to be present in sera from patients with amyotrophic lateral sclerosis (ALS) or other neurological disorders may acquire cytotoxic properties by such a mechanism. One important regulator of nervous system development is neuronal activity. At the meeting, further evidence was provided that activity has direct effects on neuronal survival and that, even when activity is not itself modulated, ion channels are involved in regulating cell death. Neurons of the isthmo-optic nucleus (ION) project to the contralateral retina where they innervate amacrine cells (Clarke). Their disposition is of particular interest in that it allows distal effects on the ION axon terminal to be analyzed quite separately from those on the cell body. Selective destruction of the amacrine cells by intraocular kainate injections during the cell death period leads to a loss of ION neurons that can be reduced by applying BDNF in the eye (20Primi M.P. Clarke P.G.H. Retrograde neurotrophin-mediated control of neurone survival in the developing nervous system.Neuroreport. 1996; 7: 473-476Crossref PubMed Scopus (26) Google Scholar). During the cell death period, intraocular application of tetrodotoxin (or saxitoxin) leads to reduced neuron death. Since a similar protective effect is seen even when the target cells have been removed, it is likely that this is a specific presynaptic effect on the ION neurons themselves. Moreover, glutamate antagonists that change the activity of retinal neurons do not affect survival in the ION. However, blocking retinal N-type Ca2+ channels does lead to reduced cell death (Clarke). Ca2+ influx into isthmo-optic terminals seems therefore to be playing an important role in the death of the ION neurons. Ca2+ also plays an important role in the regulation of cell survival by afferent activity in the avian auditory system (E. W. Rubel, University of Washington). Neurons of the nucleus magnocellularis (NM) in the brain stem receive afferent input from the cochlea via the eighth cranial nerve. Blocking the activity of the nerve with tetrodotoxin leads to a rapid (6 hr) and dramatic loss of ribosomes and protein synthesis in 30% of the NM neurons (6Hartlage-Rübsamen M. Rubel E.W. Influence of mitochondrial protein synthesis inhibition on deafferentation-induced ultrastructural changes in the nucleus magnocellularis of developing chicks.J. Comp. Neurol. 1996; 371: 471-478Crossref Scopus (18) Google Scholar). These will subsequently die, while the remaining 70% (whose protein synthesis is initially less strongly affected) will survive and recover normal metabolic activity. Afferent deprivation in vivo leads to a rapid increase in NM neuron intracellular Ca2+ levels, which precedes ribosomal degradation. In acute explant slice cultures, the intracellular Ca2+ levels in NM neurons also steadily increase, and this increase can be blocked by direct stimulation of the afferent nerve. However, the stimulation is without effect in the presence of blockers of the metabotropic glutamate receptor (mGluR), although synaptic function was not affected by the blockers (26Zirpel L. Rubel E.W. Eighth nerve activity regulates the intracellular calcium concentration of cochlear nucleus neurons in the embryonic chick via a metabotropic glutamate receptor.J. Neurophysiol., in press. 1996; Google Scholar). Furthermore, ACPD, a mGluR agonist, can mimic the effects of stimulation. Although it is not yet possible to attribute cell death to Ca2+ influx in this model directly, it is possible that in vivo, afferent activity chronically permits survival of NM neurons by acting through a mGluR to regulate Ca2+ levels (Rubel). A clue as to how Ca2+ may be working in the opposite direction to promote survival in other conditions was provided by work on purified motor neurons in culture (Comella). High K+ can keep these neurons alive, and the survival effect is blocked by Ca2+ chelators or L-channel blockers. In a correlative manner, ERK2 phosphorylation is also increased in high K+. The calmodulin antagonist W13 prevents both the hyperphosphorylation of ERK2 and the survival effects of high K+. Depolarization may therefore induce survival through a pathway involving calmodulin and ERK2 (Comella). Evidence for a less conventional involvement of ion channels in cell death in adult nematodes is provided by the members of the degenerin family, of which one of the best studied is mec-4 (M. Driscoll, Rutgers University). The degenerins show sequence homology to epithelial Na+ channels. The normal function of MEC-4 is probably as a mechanosensitive ion channel: loss-of-function mutants have nonfunctional touch cells. However, rare dominant gain-of-function mutations lead to degenerative cell death associated with swelling of the touch receptors that express mec-4 (or of other cells when mutant forms of mec-4 are expressed ectopically). Such degenerative cell death is not blocked by mutations in ced-3 or ced-4, and is clearly different from PCD on morphological grounds. Structure–function analysis suggests that the dominant mutations lead to an ion channel that cannot close completely, making the parallel with models of excitotoxicity very striking (8Hong K. Driscoll M. A transmembrane domain of the putative channel subunit MEC-4 influences mechanotransduction and neurodegeneration in C. elegans.Nature. 1994; 367: 470-473Crossref PubMed Scopus (175) Google Scholar). It is possible that this kind of cell death, which is reminiscent of autophagic cell death (Clarke), may be controlled by genes other than those that regulate PCD; a search for suppressor mutations is underway (Driscoll). However, engulfment of the cell debris seems to be under the control of the same genes as those involved in PCD. The link between mec-4 and the last experiments I will describe in this section is tenuous but provocative. Differential screening of cDNA libraries made from NMDA-treated cortical neurons has led to the identification of four new transcripts that are up-regulated by excitotoxic stimulation (J. R. Naranjo, Cajal Institute). While some of these are novel sequences, one corresponds to the sequence of gas-1 (growth arrest-specific-1), which is known to block the G0 to G1 transition in fibroblasts (4Del Sal G. Ruaro M.E. Philipson L. Schneider C. The growth arrest–specific gene, gas1, is involved in growth suppression.Cell. 1992; 70: 595-607Abstract Full Text PDF PubMed Scopus (238) Google Scholar). As expected from the cloning strategy, kainic acid administration in vivo induces expression of gas-1 in hippocampus and piriform cortex, apparently in areas where neurons will later die. Similar up-regulation is observed in X-irradiated neonatal brain or axotomized neonatal motor neurons. Furthermore, overexpression of gas-1 in cultured neurons leads to cell loss that can be prevented by Bcl2. In another paradigm, staurosporine induces up-regulation of gas-1 in neuroblastomas. When these cells are stably transfected with antisense constructs to gas-1, staurosporine does not now kill the cells, but induces them to differentiate. These results suggest that gas-1 expression is both necessary and sufficient to induce cell death. Although the function of the GAS-1 protein is not known, its primary structure is grossly reminiscent of that of MEC-4, raising the possibility that it too may be part of an ion channel (Naranjo; Driscoll). If confirmed, this would provide the first concrete basis for the exciting parallel between degenerative cell death in nematodes and mammals. Given the ubiquitous presence in a wide variety of cells of the apparatus required for apoptosis (9Jacobson M.D. Weil M. Raff M.C. Role of Ced-3/ICE-family proteases in staurosporine-induced programmed cell death.J. Cell Biol. 1996; 133: 1041-1051Crossref PubMed Scopus (358) Google Scholar), several presentations addressed the question of how and when a cell decides to undergo PCD. Discussion centered around two main questions: what decides which cell will die? and what is the sequence of molecular events that predispose, and subsequently commit, a given cell to death? In vertebrates, it is possible that death of only some cells in a large group may represent a stochastic response to the signals inducing apoptosis, although this is not in fact yet known. This is clearly not the case in nematodes and, at least in the case of certain pharyngeal neurons, specific genes called ces-1 and ces-2 control the life–death decision on a cell-specific basis (H. R. Horvitz, Massachusetts Institute of Technology). CES-2 negatively regulates ces-1. Genetic evidence suggests that ces-1 and ces-2 act through ced-9 to regulate ced-3 and ced-4, and thereby control the cell death program in these neurons alone. Other ces genes presumably control the deaths of other cell types in the nematode. It is possible that a pathway of this kind may operate in vertebrates, although the reasons for believing this are as yet indirect: ces-2 encodes a bZIP transcription factor of the PAR family, and another member of this family, hepatic leukemia factor (HLF), is activated in certain acute lymphoblastoid leukemias (11Metzstein M.M. Hengartner M.O. Tsung N. Ellis R.E. Horvitz H.R. Transcriptional regulator of programmed cell death encoded by Caenorhabditis elegans gene ces-2.Nature. 1996; 382: 545-547Crossref PubMed Scopus (137) Google Scholar). When activated, HLF can inhibit both interleukin-3-dependent and p53-mediated apoptosis of mouse pro-B lymphocytes, raising the possibility that like ces-2, HLF is involved in regulation of normal apoptosis in specific cell types. The sequence of cellular events involved in, and necessary for, the cell death pathway was the object of much discussion (Figure 1). From early events like c-jun expression (Johnson; I. Ferrer, University of Barcelona; J. M. Esquerda, University of Lleida), involved in activation and propagation of death pathways, to the late post-translational effects of NGF and Jun kinase (Tolkovsky; Greene), a fairly consistent picture seems to be emerging, with Ras playing a central role (16Nobes C.D. Reppas J.B. Markus A. Tolkovsky A.M. Active p21Ras is sufficient for rescue of rat sympathetic neurons.Neuroscience. 1996; 70: 1067-1079Crossref PubMed Scopus (41) Google Scholar). The commitment of a cell to the death process is thought to occur just before the execution of the apoptotic program, and seems to be very near the point at which Bcl2 and Bax act (Johnson). It is likely for several reasons that the cysteine proteases act at even later stages. First, genetic analysis in Caenorhabditis elegans puts ced-3 downstream of ced-9, even though another novel gene product, ced-8, may subsequently be required to regulate the cell death process or its timing (Horvitz). Second, peptide protease inhibitors can inhibit staurosporine-induced death even when added 2 hr after the drug, at the time at which the first morphological alterations are discernible (Jacobson). The fact that these inhibitors are active at much later stages than cycloheximide in preventing death of sympathetic neurons suggests that the proteases are not the proteins whose synthesis is necessary for cell death (Johnson). Finally, proteolytic cleavages of poly(ADP–ribose)polymerase (PARP) and of CPP32 itself are both prevented by overexpression of BCL2 (Jacobson; Bredesen). These are two members of a family of proteins known to be important regulators of the apoptotic cascade. The molecular mechanism of their action is currently unknown, though they may serve as pores of unknown specificity in the mitochondrial membrane. Classically, Bcl2 (and its nematode homolog ced-9) have been demonstrated to have antiapoptotic properties, while Bax tends to enhance cell death. However, two exceptions to this simple model were discussed at the meeting. First, in C. elegans, ced-9 can in some circumstances act as a killer protein, perhaps by inhibiting the production of a novel “long” splice variant of ced-4, which in contrast with the predominant short form of ced-4, can protect against PCD (22Shaham S. Horvitz H.R. An alternatively-spliced C. elegans ced-4 RNA encodes a novel cell-death inhibitor.Cell. 1996; 86: 201-208Abstract Full Text Full Text PDF PubMed Scopus (123) Google Scholar). Second, when overexpressed in cultured primary sensory neurons from the chicken embryo, BAX can promote survival (14Middleton G. Nunez G. Davies A.M. Bax promotes neuronal survival and antagonizes the survival effects of trophic factors.Development. 1996; 122: 695-701Crossref PubMed Google Scholar). Several investigators reported studies on Bax and Bcl2 knockout mice. Their results clearly illustrated the particular importance of these genes in nervous system development. Mice in which the Bcl2 gene has been disrupted show gross abnormalities in relatively few tissues. However, careful cell counting has revealed significant, gene dosage–dependent neuronal loss in trigeminal sensory neurons (Davies) and in dorsal root ganglion sensory, sympathetic, and facial motor populations (T. Michaelidis, Max-Planck-Institute for Psychiatry), demonstrating that Bcl2 is absolutely required for the survival of some neurons. These observations probably represent cell-autonomous effects of the mutation, since neurons that normally express higher levels of BCL2 protein tend to be preferentially eliminated in the knockout mice (Michaelidis), and embryonic sensory neurons isolated from the Bcl2−/− mice show altered survival responses to neurotrophins in culture (Davies). Not all neurons apparently change their requirements for trophic factors in the absence of Bcl2. BDNF or CNTF administered to axotomized neonatal facial motor neurons in vivo had similar survival effects whether or not the Bcl2 gene was inactivated (13Michaelidis M.T. Sendtner M. Cooper J.D. Airaksinen M.S. Holtmann B. Meyer M. Thoenen H. Inactivation of bcl-2 results in progressive degeneration of motoneurons, sympathetic and sensory neurons during early postnatal development.Neuron. 1996; 17: 75-89Abstract Full Text Full Text PDF PubMed Scopus (239) Google Scholar). The effects of Bcl2 in trigeminal sensory neurons are apparent during the natural cell death period (Davies), whereas loss of dorsal root ganglion sensory, motor, and sympathetic neurons occurs immediately following this period (Michaelidis). These findings indicate a crucial role of endogenous Bcl2 at a critical stage of neuronal development, during or shortly after the period of naturally occurring cell death. Bax knockout mice, too, show only a minor phenotype by gross analysis, and indeed most naturally occurring and induced apoptosis in the immune system seems to occur normally. However, there are profound alterations in the survival of neurons from these mice (3Deckwerth T.L. Elliott J.L. Knudson C.M. Johnson Jr., E.M. Snider W.D. Korsmeyer S.J. BAX is required for neuronal death after trophic factor deprivation and during development.Neuron. 1996; 17: 401-411Abstract Full Text Full Text PDF PubMed Scopus (643) Google Scholar). Remarkably, sympathetic neurons from Bax−/− animals will survive for weeks in culture in the absence of NGF, although they shrink to about 20% of their normal volume (this can be restored by NGF). Fewer facial motor neurons than normal are lost by PCD in these mice, and neonatal axotomy does not lead to motor neuron loss (Johnson). Resistance to axotomy has already been reported for motoneurons from transgenic mice overexpressing Bcl2, but in that case, it was possible that high levels of BCL2 were having only a pharmacological effect. The new results provide an important demonstration that Bax expression is absolutely necessary for axotomized motor neurons to be able to die. Overall, these new results fit in well with the roles deduced for Bcl2 and Bax from other experiments. Strikingly, the results from the knockout mice demonstrate that despite the existence of several family members, the physiological roles of Bax and Bcl2 are far from redundant in the nervous system. As first deduced from analysis of the ced-3 mutation in C. elegans, cysteine proteases play a central effector role in the cell death program. Since the original description of ICE, more than ten family members have been discovered. They fall into three groups: the ICE subfamily, the CPP32 subfamily, and the NEDD2/ICH subfamily. Although evidence to document their essential role in apoptosis continues to accumulate, their mode of action is poorly understood. In particular, most of the key substrates on which they act (with the exception of themselves) to cause the morphological changes characteristic of apoptosis remain to be identified. A recurrent leitmotiv of presentations at the meeting was the use of peptide or polypeptide inhibitors to demonstrate that such proteases are required for a given degenerative process, or to distinguish between the different classes of protease involved (Oppenheim; Jacobson; Greene; Johnson; Sadoul; Horvitz; White; L. Stefanis, Columbia University). The range of reagents available is now considerable; some, such as the membrane-permeant Boc–Asp–fmk (BAF), and z-VAD, potently inhibit multiple members of the family, while others such as z-DEVD–fmk are more specific for members of the CPP32 family. The results obtained point to selective involvement of different proteases in different cell death processes, even in the same cell type. One example of this comes from the analysis of motor neuron survival in chicken embryos (Oppenheim). Whereas naturally occurring cell death can be inhibited by application in ovo of the protease inhibitor YVAD (15Milligan C.E. Prevette D. Yaginuma H. Homma S. Cardwell C. Fritz L.C. Tomaselli K.J. Oppenheim R.W. Schwartz L.M. Peptide inhibitors of the ICE protease family arrest programmed cell death of motoneurons in vivo and in vitro.Neuron. 1995; 15: 385-393Abstract Full Text PDF PubMed Scopus (293) Google Scholar), the motor neuron death induced by limb removal is not affected by the same inhibitor. Another example of alternative use of proteases came from PC12 cells, which can be made to die either by NGF deprivation or by lowering superoxide dismutase (SOD) levels using antisense oligonucleotides (Greene). Not surprisingly, death induced by each treatment can be blocked by a series of reagents related to the initial insult (23Troy C.M. Derossi D. Prochiantz A. Greene L.A. Shelanski M.L. Downregulation of Cu/Zn superoxide dismutase leads to cell death via the nitric oxide–peroxynitrite pathway.J. Neurosci. 1996; 16: 253-261Crossref PubMed Google Scholar). As also expected, the two pathways converge on a death program that involves cysteine proteases and is blocked by wide-spectrum inhibitors such as z-VAD. The unexpected finding is that different proteases are involved in death induced by the two treatments. Death of NGF-deprived PC12 cells or sympathetic neurons seems to involve a NEDD-like protease, whereas SOD-depleted PC12 cells are protected from apoptosis by inhibitors of the ICE subfamily (Greene). Surprisingly, in the latter paradigm, pro-interleukin 1β (IL-1β) itself is proposed to be an important substrate for the ICE-like protease, since IL-1β is released into the medium following SOD depletion and can exacerbate the effects of SOD-depletion (24Troy C.M. Stefanis L. Prochiantz A. Greene L.A. Shelanski M.L. The contrasting roles of ICE family proteases and interleukin-1β in apoptosis induced by trophic factor withdrawal and by copper/zinc superoxide dismutase down-regulation.Proc. Natl. Acad. Sci. USA. 1996; 93: 5635-5640Crossref PubMed Scopus (190) Google Scholar). It will be interesting to see in what other cell types the latter mechanism is used, as sympathetic neurons in normal culture conditions do not express ICE itself and are not killed by IL-1β (Sadoul). However, as a possible parallel to the results in NGF-deprived PC12 cells, overexpression of ICE itself following microinjection into sympathetic neurons grown in NGF does not affect survival, whereas overexpression of NEDD2 kills the neurons (Sadoul). PCD has been a central topic of research on the developing nervous system for over 50 years, and never more so than now. However, in spite of the quantity of new data that has been amassed, we still do not know in most cases the functional significance of the PCD observed nor how it is regulated in vivo. The workshop provided fascinating insights into the interactions between exogenous and cell-autonomous influences on neural cells' decision to live or die. However, many links are missing at all levels: unknown trophic factors, mode of action of the members of the Bcl2 family, substrates of the cysteine proteases, genes involved in different kinds of cell death, etc. Although the progressive discovery of these and other actors may initially complicate the field, complexity is probably the price to pay for sounder hypotheses, and more reliable experimental results." @default.
• W2022101852 created "2016-06-24" @default.
• W2022101852 creator A5030689442 @default.
• W2022101852 date "1996-10-01" @default.
• W2022101852 modified "2023-10-13" @default.
• W2022101852 title "Programmed Cell Death in the Developing Nervous System" @default.
• W2022101852 cites W1979160989 @default.
• W2022101852 cites W1984802438 @default.
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