Developmental cell death

Clarke, P. G. (1990) Developmental cell death morphological diversity and multiple mechanisms. Anat. Embryol. 181,195-213. 

Thus, cell death is accompanied by similar morphological changes in a wide variety of circumstances. However, as we shall see below, they do not involve the same mechanisms. In this context, one should be careful not to use the functional terms programmed or developmental cell death, to denote other types of cell death of which the end result is apoptosis but which are clearly not developmental. 

Many models are currently being used to study apoptosis. These include the study of growth factor-deprived cell cultures, cells treated with radiation or cytoxic agents, vims-infected cells and many models in vivo and in vitro of programmed or developmental cell death. In this review, we will concentrate on models of developmental cell death. These include developmental cell death in the nematode, C. elegans, primary cultures of neurotrophic-dependent neurons, the pheo-chromocytoma cell line, PC 12, and primary cultures of immature thymocytes. Studies involving these models of cell death have defined molecules and pathways that may be important in a wide variety of types of apoptosis. 

These mechanisms of cell death are poorly understood but probably include (1) an antigen-specific mechanism which involves triggering of the TCR, CD4 and CD8, as well as MHC/antigen presenting cells and (2) non-antigen-specific mechanisms which involve the membrane receptor Fas (see Section 3.2) (Kisielow et al., 1988a,b Sha et al., 1988 Smith et al., 1989 Swat et al., 1991 Debatin, 1994 Debatin et al., 1994 McConkey et al., 1994 Kisielow and von Boehmer, 1995). Activation of the TCR and Fas on thymocytes forms the basis of models of developmental cell death. 

In mature T cells, activation of the TCR induces proliferation via an autocrine mechanism by stimulating the synthesis of both IL-2 and IL-2 receptor (Meuer et al., 1984). On withdrawal of IL-2 these cell undergo apoptosis by a mechanism that requires synthesis of both protein and RNA (Duke and Cohen, 1986). However, if IL-2 or other growth factors are available, these cells proliferate for 3-4 days, after which time they undergo apoptosis, a phenomenon referred to as activation-induced cell death (AICD). Protein and RNA synthesis is required at the time of activation for AICD to proceed (Shi et al., 1989 Ucker et al., 1989 Green and Scott, 1994). Although not strictly developmental cell death, AICD has been used to study the involvement of molecules such as Fas (see Section 3.2) and Myc (see Section 5.2) in the T cell. 

In the preceding sections, we have described the major models used to study developmental cell death. We will now discuss the cell death pathways implicated by these models, which lead to apoptosis. For convenience, apoptosis may be subdivided into the initial signalling events, the apoptotic signal transduction pathways and the terminal events involved in the observed phenotypic changes. 

Cell surface receptors may also induce apoptosis when activated following ligand binding. The two best-characterised receptors which do this are the receptor. Fas, and the tumour necrosis factor (TNF) receptor. Of these. Fas is involved in developmental cell death and will be considered in detail here (for a recent review on Fas-mediated apoptosis see Nagata and Golstein, 1995). 

Recently, we have shown that c-Jun but not c-Fos protein is expressed in rat sympathetic neurons undergoing normal developmental cell death in vivo. C-Jun was expressed exclusively in apoptotic neurons that had proceeded to the stage of chromatin condensation (Messina, 1994). 

From the above discussion, it appears that c-Fos is not indispensible in developmental cell death although its transient induction correlates with apoptosis in a number of experimental systems. On the other hand, c-Jun is essential during development which may involve a role in developmental cell death. Although such a role has yet to be proven, sustained induction of c-Jun correlates with apoptosis in a number of experimental systems. 

It has not yet been established whether c-Myc is involved in developmental cell death in vivo. Circumstantial evidence for c-Myc involvement comes from the following observations (1) c-myc mRNA is increased following activation of the TCR in immature thymocytes (Riegel et al, 1990), (2) c-myc antisense oligonucleotides inhibit TCR-induced apoptosis in T cell hybridomas (Green et al, 1992 Shi et al, 1992) and (3) Myc-Max heterodimers are necessary for AICD in these cells (Bissonnette et al.,... 

The involvement of Bcl-2-like proteins in developmental cell death has been extended to other model systems. In granulosa cells of ovarian follicles, apoptosis has been shown to be associated with an increase in box mRNA and a decrease in bcl-Xi mRNA, but without change in bcl-2 expression (Tilly et al., 1995), consistent with the presumed involvement of these proteins in the above-mentioned models. 

Lack of involvement ofp53 in developmental cell death... 

Apoptosis can be conveniently divided into three phases (1) the initial stimulus to undergo cell death,(2) the central signalling events and (3) the final morphological changes. In developmental cell death, the first phase may be intrinsic to the cell s genetic programming, or it may be induced... 

Messina, A. (1994) Expression of C-Jun protein during developmental cell death in sympathetic neurons. Proc. Aust. Physiol. Pharmacol. Soc., 25 109P. 

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