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Gartner, A., Milstein, S., Ahmed, S., Hodgkin, J. & Hengartner, M. O. A conserved checkpoint pathway mediates DNA damage-induced apoptosis and cell cycle ...
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Apoptosis in development Pascal Meier*‡, Andrew Finch† & Gerard Evan† *Signal Transduction Laboratory, Imperial Cancer Research Fund, 44 Lincoln’s Inn Fields, London WC2A 3PX, UK †UCSF Cancer Center, 2340 Sutter Street, San Francisco, California 94143-0875, USA (e-mail: [email protected]; [email protected]) ‡Present address: The Breakthrough Toby Robins Breast Cancer Research Centre, Institute of Cancer Research, Chester Beatty Laboratories, Fulham Road, London SW3 6JB, UK (e-mail: [email protected])

Essential to the construction, maintenance and repair of tissues is the ability to induce suicide of supernumerary, misplaced or damaged cells with high specificity and efficiency. Study of three principal organisms — the nematode, fruitfly and mouse — indicate that cell suicide is implemented through the activation of an evolutionarily conserved molecular programme intrinsic to all metazoan cells. Dysfunctions in the regulation or execution of cell suicide are implicated in a wide range of developmental abnormalities and diseases.


hose interested in the ‘Big Dig’, the city of Boston’s heroic attempt to bury Interstate 93 beneath its pavements while maintaining a passable stab at business-as-usual above, will be well acquainted with the idea that major construction entails a substantial amount of demolition. So too in animal development: during the ontogeny of many organs, cells are over-produced only to be etched or whittled away to generate the rococo structures of functional tissues. Early distaste among biologists for the ‘wastefulness’ of such a process has given away to the recognition that the ability to ablate cells is as essential a constructive process in animal ontogeny as are the abilities to replicate and differentiate them. After all, most animals thrive in a sea of energy and profligacy with their component cells is a small price to pay for ability to move around and propagate. It is highly unlikely that the peacock, upon encountering the peahen of his dreams, demurs to ponder the energetic cost of his outrageous tail. It is now clear that physiological cell death is an essential component of animal development, important for establishment and, in vertebrates at least, maintenance of tissue architecture. A general modus operandi of metazoan development is the over-production of excess cells followed by an apoptotic culling during later stages of development to match the relative number of cells of different types to achieve proper organ function1. Thus, during animal development, numerous structures are formed that are later removed by apoptosis. This enables greater flexibility as primordial structures can be adapted for different functions at various stages of life or in different sexes. Thus, the Müllerian duct gives rise to the uterus and oviduct in females but it is not needed in males and so is consequently removed. On the other hand, the Wolffian duct is the source of male reproductive organs and is deleted in females. Organisms are like many modern computer programs, full of remnant code that was once used in an ancestral incarnation or that runs irrelevant routines that nobody needs. During development, apoptosis is frequently used to expunge such structures. For instance, early in vertebrate development, the pronephric kidney tubules arise from the nephrogenic mesenchyme. Although these pronephric tubules form functioning kidneys in fish and in amphibian larvae, they are not active in mammals and degenerate2. Similarly, during insect and amphibian metamorphosis, apoptosis ablates cells that are no longer needed such as muscles and neurons essential for larval locomotion in insects or the amphibian tadpole tail. 796

Apoptosis also acts as part of a quality-control and repair mechanism that contributes to the high level of plasticity during development by compensating for many genetic or stochastic developmental errors. For example, Drosophila embryos with extra doses of the morphogen bicoid (bcd) gene show sever