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Cell Death Returns to Its Roots Cell-Death Researchers Are Looking Back at an Old Question, As Interest Isrevived in Exploring the Role of Cell Death in Morphogenesis

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Cell Death Returns to Its Roots Cell-Death Researchers Are Looking Back at an Old Question, As Interest Isrevived in Exploring the Role of Cell Death in Morphogenesis View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Elsevier - Publisher Connector KRISTIN WHITE MORPHOGENESIS Cell death returns to its roots Cell-death researchers are looking back at an old question, as interest isrevived in exploring the role of cell death in morphogenesis. Although the field of programmed cell death (apoptosis) rhombomeres r3 and r4 induces the production of BMP-4 has seen an explosion of popularity in the last decade, it has in r3. BMP-4 is a member of the transforming growth fac- its foundations in the work of developmental biologists in tor 3 (TGF-3) superfamily of secreted signalling molecules, the first half of the century. They observed that cell death and has been shown to play a role in several developmental often accompanied developmental processes. Gliicksmann processes. BMP-4 activates apoptosis of the dorsal cells of [1] compiled these observations in a review published in rhombomeres r3 and r5, possibly through the homeobox 1951. He classified the majority of naturally occurring cell gene msx-2, expression of which is up-regulated in deaths as morphogenetic - having to do with changes in response to BMP-4 (Fig. 1). The addition of BMP-4 to r3 the form of organs or tissues. This classification was based explants, but not to r4 explants, turns on msx-2 and results on the colocalization of cell deaths with events that in apoptosis. This indicates that the r3 explants not only appeared to shape the tissue, but it was not clear if these produce BMP-4, but are also primed to respond to it, deaths were actually required for morphogenesis or simply possibly by expression of the BMP-4 receptor. accompanied it. Despite considerable progress in character- izing the morphology and biochemistry of programmed These results suggest that interactions within the develop- cell death, we still understand relatively little about the ing neuroepithelium act to divide the neural crest into dis- function of cell death in morphogenesis. tinct streams, which are responsible for patterning the head. It seems likely head development would not occur Much of the cell death that occurs during development normally without these deaths, but it is conceivable that happens at very low levels, over a long period of time [2], excess cells could be accommodated. For example, cell- making it particularly hard to judge what function these death-defective mutants of the nematode Caenorhabditis deaths serve. The correlation of morphogenetic events and elegans have 14 % more somatic cells than normal, yet they cell death is made more easily when the deaths take place produce essentially normal animals [6]. As John Saunders relatively rapidly, in a defined group of cells. Lumsden and [7] warned, "...one must not accept without experimenta- his colleagues [3] have described such a system, the cranial tion that for a particular morphogenetic ... process, those neural crest of the chick. Furthermore, they have identi- deaths accompanying it, regardless of their prominence, are fied some of the molecular mechanisms that induce death requisite for its achievement". in these cells. This may eventually allow the function of these deaths to be evaluated directly. The only way that the cell death can be shown to be func- tionally required is to prevent it from occurring. There are Neural crest cells originate from the dorsal region of the several possible approaches to this problem. Cell death can hindbrain. These cells migrate ventrally to contribute to be eliminated by mutations that block apoptosis ubiqui- both neural and mesenchymal tissues of the head, and also tously or in a particular tissue. Another approach is to act to pattern the mesoderm in this region [4]. Neural identify steps in the cell-death pathway that can be experi- crest cells emerge from the hindbrain in three streams, mentally blocked, either by interfering with the induction which arise from discrete segments of the neural tube, of the death, or by the introduction of anti-apoptotic called rhombomeres, and populate distinct head structures. functions. These functions include the proto-oncogene Rhombomeres rl plus r2, r4 and r6, which produce crest bcl-2 and various viral anti-apoptotic genes. For example, cells, alternate with rhombomeres r3 and r5, which do not the death of the neural crest cells in rhombomeres r3 and produce crest cells. The dorsal neural tube in rhom- r5 might be prevented by interfering with the induction of bomeres r3 and r5 instead undergoes significant apoptosis. BMP-4, or with its action. Graham et al. [5] have shown that the death of the neural crest cells in r3 and r5 depends on interaction with their In Drosophila, the use of cell-death-defective mutants neighboring rhombomeres. When rhombomeres r3 and r5 and the introduction of anti-apoptotic functions have are explanted alone, they produce migrating neural crest allowed researchers to look at the role of cell death in the cells, but when placed in culture with their neighboring development of the eye. Mutants have been identified that even-numbered rhombomeres, they do not. These results eliminate the programmed cell death of certain cells in the can be reproduced in vivo by surgical manipulation of the retina, resulting in 'rough' eyes [8]. These deaths can also rhombomere order. be blocked by the introduction of the baculovirus anti- apoptotic gene p3 5 , with the same results [9]. In the In their recent paper [3], Lumsden and colleagues have future, the role of cell death in the development of other characterized some of the molecules involved in this tissues of this organism can be addressed using a combina- process. They have found that the interaction between tion of these methods, particularly as a mutation has been © Current Biology 1995, Vol 5 No 4 371 372 Current Biology 1995, Vol 5 No 4 Fig. 1. Cell interactions that lead to sculpting of the neural crest. In this schematic cross-section of the neural tube in the developing hindbrain, cells in the shaded dorsal area are the source of the neural crest. These cells migrate ventrally to contribute to neural and mesenchymal tissue of the head. Interactions between rhombomeres (segments of the neural tube) lead to the death of crest cells in rhombomeres r3 and r5, and sculpt the migrating neural crest into three streams which populate and pattern distinct head structures. described that eliminates all cell deaths during normal Obviously, there are still many more questions than answers embryonic development [10]. about the role that cell death plays in morphogenesis. Our expanding knowledge about the molecular mechanisms of In several recent papers, these strategies have been applied programmed cell death has led to the development of the to vertebrates in attempts to correlate defects in tools necessary to address this issue. These tools range from morphogenesis with cell-death suppression. A number of cell-death-defective mutations, to the characterization of a investigators have chosen to study cell death in the variety of anti-apoptotic functions, to the identification of interdigital region of the mouse or chick limb. This death tissue-specific inducers of cell death. The availability of has long been proposed to be responsible for the these tools should make the morphogenetic role of cell separation of the digits of the hands and feet. Early work death an active area of research for the future. [7] showed that injection of chick embryos with the dye Janus green blocked interdigital cell death and resulted References 1. GlOcksmann A: Cell deathsin normal vertebrate ontogeny. Biol Rev in webbing between the toes. Two mutations have 1951, 26:59-86. recently been shown to block this interdigital death in 2. Raff MC, Barres BA, Burne JF, Coles HSR, Ishizaki Y, Jacobson MD: Programmed cell death and the control of cell survival. Phil Trans R Soc mice, and to result in abnormal appendages. In the Lond IBiol] 1994, 345:265-268. Hammertoe mutant, cell death is lacking between digits 2 3. Graham A, Francis-West P, Brickell P, Lumsden A: The signaling mol- and 5 during development, and the mutants show ecule BMP4 mediates apoptosis in the rhombencephalic neural crest. Nature 1994, 372:684-686. webbing between these digits [11]. A similar defect in cell 4. Lumsden A, Sprewson N, Graham A: Segmental origin and migration of death is seen in the Fused toes mutant, although the adult neural crest cells in the hindbrain region of the chick embryo. Development 1991, 113:1281-1291. phenotype is more dramatic, with fusion of the bones of 5. Graham A, Heyman , Lumsden A: Even-numbered rhombomeres con- the fore limbs [12]. Taken together, these results indicate trol the apoptotic elimination of neural crest cells from odd-numbered that interdigital death is required for the proper rhombomeres in the chick hindbrain. Development 1993, 119:233-245. 6. Ellis H, Horvitz HR: Genetic control of programmed cell death in the development of the foot. nematode C. elegans. Cell 1986, 44:817-829. 7. Saunders JW Jr: Death in embryonic systems. Science 1966, 154:604-612. 8. Wolff T, Ready DF: Cell death in normal and rough eye mutants of Anti-apoptotic functions have also been used to address Drosophila. Development 1991, 113:825-839. questions of morphogenesis. The product of the bcl-2 9. Hay BA, Wolff T, Rubin GMR: Expression of baculovirus P35 gene has been shown to block cell death in a variety of prevents cell death in Drosophila. Development 1994, 120:2121-2129. 10. White K, Grether ME, Abrams JM, Young L, Farrell K, Steller H: Genetic cell types. When bcl-2 is ubiquitously expressed early in control of programmed cell death in Drosophila. Science 1994, mouse embryonic development, certain programmed cell 264:677-683.
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