Dynamic Development


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Programmed Cell Death in Development

Why must some cells die for the good of the embryo?

Programmed cell death (PCD) is an important mechanism in both development and homeostasis in adult tissues for the removal of either superfluous, infected, transformed or damaged cells by activation of an intrinsic suicide program. One form of PCD is apoptosis, which is characterized by maintenance of intact cell membranes during the suicide process so as to allow adjacent cells to engulf the dying cell so that it does not release its contents and trigger a local inflammatory reaction. Cells undergoing apoptosis usually exhibit a characteristic morphology, including fragmentation of the cell into membrane-bound apoptotic bodies, nuclear and cytoplasmic condensation and endolytic cleavage of the DNA into small oligonucleosomal fragments (Steller, 1995). The cells or fragments are then phagocytosed by macrophages.

Signals that can trigger apoptosis can include

  • lineage information
  • damage due to ionizing radiation or viral infection
  • extracellular signals.

Extrinsic signals may either suppress or promote apoptosis, and the same signals may promote survival in one cell type and invoke the suicide program in others (Steller, 1995).

Invocation of the suicide program involves the synthesis of specific messenger RNA molecules and their translation. PCD can sometimes be suppressed by inhibiting transcription or translation (Steller, 1995), which provides evidence that cell death is mediated by intrinsic cellular mechanisms.

Cell death is currently the subject of considerable research activity. This interest stems, in part, from the potential for understanding oncogenesis and the possibility of exploiting the cell death program for therapeutic purposes. For example, inhibition of cell death might contribute to oncogenesis by promoting cell survival instead of death. Likewise, triggering cell death might provide the means for eliminating unwanted cells (e.g., tumor cells).

Recognition of PCD as a developmental mechanism dates back to the 1930's. Developmental processes that involve PCD include:

  • Elimination of transitory organs and tissues. Examples include phylogenetic vestiges (pronephros and mesonephros in higher vertebrates), anuran tails and gills and larval organs of holometabolous insects.
  • Tissue remodeling. Vertebrate limb bud development (Fig. 11.42, Saunders, 1982; Fig. 1, Saunders, 1966) is an example. If PCD fails, in formation of the digits, digits remain joined by soft tissue. Compare, for example, the situation in the chick and duck hind limbs. If chick limb mesoderm is combined with duck ectoderm, PCD fails and the digits remain joined (Saunders, 1966). This observation implicates the ectoderm in providing the signal to trigger PCD. Another example is formation of heart loops during vertebrate development. Depletion of cells in spinal ganglia occurs during development of the chick embryo. As shown in Table 11.1 (Saunders, 1982), there is precise chronological and spatial control over this process. Interestingly, injections of nerve growth factor reduce the frequency of cell death in the spinal ganglia. This observation provides a link between growth control and PCD.

Much of our current knowledge about the molecular genetics of PCD comes from work on Caenorhabditis elegans. The adult hermaphrodite C. elegans forms 1090 somatic cells, of which 131 die by apoptosis. There are four stages in apoptosis in worms (Steller, 1995):

  • decision whether a cell should die or assume another fate;
  • death;
  • engulfment of the dead cell by phagocytes;
  • degradation of the engulfed corpse.

A number of genes have been identified that regulate these processes in worms (see Fig. 1, Steller, 1995). Mutations affecting the final three stages affect all somatic cells, whereas genes affecting the death verdict affect very few cells. Execution itself is mediated by ced-3, ced-4 and ced-9 (ced = cell death defective).

Cloning of the apoptotic genes of C. elegans and their characterization have led to considerable understanding of the molecular events of apoptosis and to the identification of mammalian homologues of the apoptotic effectors. For example, ced-9 and ced-3 are homologous to the protooncogene bcl-2 and ice (interleukin-1ß-converting enzyme, respectively.

Why do some cells die and others survive? There is evidence from work on higher organisms that extrinsic signals may protect cells from apoptosis by suppressing the suicide program (Raff, 1992). For example, the survival of developing neurons may depend upon neurotrophic factors secreted by their targets; a failure to receive sufficient stimulation results in death.

What is the advantage to the organism of using extrinsic signaling to sustain cell survival? One possibility is that it could provide a simple system to eliminate cells that end up in the wrong place; without a signal to sustain them, rogue cells would be eliminated (Raff, 1992). Consider primordial germ cells, for example. In mammals, they originate in the hindgut and must migrate to the genital ridges, where they form the gametes. Those that fail to reach the genital ridges are eliminated, presumably because they are deprived of the signal (Steel factor) that is required for their survival in the genital ridges (De Felici and Pesce, 1994).

A disadvantage to the organism of the mechanism that necessitates signaling to prevent apoptosis is that its failure by mutation can lead to the survival of unwanted cells, which - paradoxically - can lead to death of the organism itself. On the other hand, an opportunity is presented by such a mechanism to allow investigators to devise means for targeting unwanted cells for destruction. This might be accomplished by harnessing tumor necrosis factor (TNF), which triggers apoptosis in some target cells. Prostate cancer is an example. The survival of prostate cells is dependent upon androgens; androgen depletion leads to a reduction in cell number by apoptosis. Recently, the dependence of prostate cells on androgens to avoid cell death has been exploited therapeutically by the use of androgen ablation to invoke apoptosis in prostate cancer cells and prolong survival in men with prostate cancer.

Significantly, resistance to androgen depletion correlates with overexpression of bcl-2, the human ced-9 homologue that acts as a brake on prostate cancer cell apoptosis (Raffo et al., 1995). Thus, escape from androgen sensitivity by overexpression of bcl-2 in a subset of prostate cancer cells leads to proliferation of these cells and, ultimately, death of the patient. If bcl-2 could be down-regulated, apoptosis of these cells could be invoked and the cancer controlled.

Ironically, there may be an inverse correlation between cell death and survival of the organism. Exploitation of this relationship holds much promise for therapeutic control of diseases such as cancer.

Learning Objectives

  • What are the characteristics of apoptosis?
  • What is the evidence that apoptosis is mediated by intrinsic cellular mechanisms?
  • Discuss examples of apoptosis as a mechanism of morphogenesis.
  • Describe the phases of cell death.
  • What are the mammalian homologues of ced-9 and ced-3, repectively?
  • Where in the cell death program do bcl-2, p53 and ICE function?
  • How might interference with the cell death program be manifest?

Digging Deeper:

Links to Related Material

A Brief Introduction to Apoptosis

Programmed Cell Death and Cancer

Apoptosis on the Net

Apoptosis/Programmed Cell Death Home Page

Molecular Pharmacology Journal Club :

  • Discussion of Inhibition of Bax Channel-Forming Activity by Bcl-2
    Authors: Antonsson, B., Conti, F., Ciavatta, A., Montessuit, S., Lewis, S., Marinou, I., Bernasconi, L., Bernard, A., Mermod, J-J., Mazzei, G., Maundrell, K., Gambale, F., Sadoul, R., Martinou, J-J. Source: Science Vol 277, July 18, 1997, pages 370-372.

Science Special Report on Apoptosis

Survivin: A novel anti-apoptosis gene

Recent Literature

Barinaga, M. 1996. Forging a path to cell death. Science 273: 735-737.

Diez-Roux, G. and Lang, R.A. 1997. Macrophages induce apoptosis in normal cells in vivo. Development 124: 3633-3638.

Gura, T. 1997. How TRAIL kills cancer cells, but not normal cells. Science 277: 768.

Jiang, C., Baehrecke, E. H. and Thummel, C. S. 1997. Steroid regulated programmed cell death during Drosophila metamorphosis.

Liu, X., Zoa, H., Slaughter, C. and Wang, X. 1997. DFF, a heterodimeric protein that functions downstream of caspase-3 to trigger DNA fragmentation during apoptosis. Cell 89: 175-184.

Metcalfe, A. and Streuli, C.. 1997. Epithelial apoptosis. BioEssays 19: 711-720.

Pan, G., Ni, J., Wei, Y.-F., Yu, G.-l., Gentz, R. and Dixit, V.M. 1997. An antagonist decoy receptor and a death domain-containing receptor for TRAIL. Science 277: 815-818.

Porter, A.G., Ng, P. and Jänicke. 1997. Death substrates come alive. BioEssays 19: 501-507.

Sheridan, J.P., Marsters, S.A., Pitti, R.M., Gurney, A., Skubatch, M., Baldwin, D., Ramakrishnan, L., Gray, C.L., Baker, K., Wood, W.I., Goddard, A.D., Godowski, P. and Ashkenazi, A. 1997. Control of TRAIL-induced apoptosis by a family of signaling and decoy receptors. Science 277: 818-821.

Stack, J.H. and Newport, J.W. 1997. Developmentally regulated activation of apoptosis early in Xenopus gastrulation results in cyclin A degradation during interphase of the cell cycle. Development 124: 3185-3195.

White, E. 1997. Life, death and the pursuit of apoptosis. Genes & Dev. 10: 1-15.

White, K., M.E. Grether, J.M. Abrams, L. Young, K. Farrell and H. Steller 1994. Genetic control of programmed cell death in Drosophila. Science 264: 677-683.


De Felici, M. and M. Pesce. 1994. Growth factors in mouse primordial germ cell migration and
proliferation. Prog Growth Factor Res 5: 135-143.

Hengartner, M.O., R.E. Ellis and H.R. Horvitz. 1992. Caenorhabditis elegans gene ced-9 protects cells from programmed cell death. Nature 356: 494-499.

Raff, M.C. 1992. Social controls on cell survival and cell death. Nature 356: 397-400.

Raffo, A.J., H. Perlman, M. W. Chen, M. L. Day, J. S. Streitman and R. Buttyan. 1995. Overexpression of bcl-2 protects prostate cancer cells from apoptosis in vitro and confers resistance to androgen depletion in vivo. Cancer Res 55: 4438-4445.

Saunders, J.W. 1966. Death in Embryonic Systems. Science 154: 604-612.

Saunders, J.W., Jr. 1982. Developmental Biology. Macmillan. New York.

Steller, H. 1995. Mechanisms and genes of cellular suicide. Science 267: 1445-1449.

Dynamic Development at a Glance
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This material may be reproduced for educational purposes only provided credit is given to the original source.
Leon Browder & Laurie Iten (Ed.) Dynamic Development
Last revised Tuesday, July 21, 1998