or foot is missing. Tabin (1998) recently proposed that thalidomide reduces cell proliferation in the PZ, by means yet unknown, and the few cells that remain there in prolonged contact with FGF8 secreted by the AER are specified as hand or foot cells, the last normally to emerge from the zone. This is an example of an incisive prediction about a long-known toxicant made on the basis of recent knowledge. Yet, the chemical basis for thalidomide’s specific effect on cell proliferation in the PZ escapes even a proposal at this time, and so the hypothesis is incomplete. Stephens and Fillmore (2000) have suggested that thalidomide interferes with integrin gene expression in limb bud mesenchyme cells and, thereby, with their ability to stimulate angiogenesis at the level needed for continued rapid proliferation.

The capacity of the limb bud to develop normally after injury has been studied. Large numbers of cells can be removed at early stages, and as long as representatives remain of the AER, ZPA, and PZ, development will be normal. Immigrating muscle cells from any myotome will enter and adapt to the limb bud, and nerves from any spinal cord level will enter and make neuromuscular connections, although the CNS circuitry of that level may not be appropriate for normal limb movement. The robustness of limb development, like that of other parts of the body, is substantial, because each of the interactive cell groups is much larger than minimally necessary and is capable of proliferation. Robustness is not unlimited, however, and total removal of a key signaling or responding group is deleterious. Regenerating limbs, such as those of newts, have surmounted even that limit, but they are the exception among vertebrates.


This committee has been asked to evaluate the state-of the-science for elucidating mechanisms of developmental toxicity. It seems self-evident that the knowledge about the basic processes of development provides developmental biologists with an understanding of normal development not even thought possible a decade ago, and also provides developmental toxicologists with improved tools to understand the mechanisms by which chemicals cause abnormal development.

In the last decade, great advances have been made in the understanding of developmental processes on a molecular level in model organisms, such as Drosophila and C. elegans, and in several vertebrates, including the mouse. For the first time, molecular components and their functional interactions have been identified. Developmental processes can be described for the first time as organized networks of these components and their functions. The examples examined so far primarily concern early development before organogenesis but also organogenesis in a few cases. Cell-cell interactions by way of intercellular signals are pervasively and repeatedly used. In all aspects of development, including organogenesis and cytodifferentiation, signaling is expected to be of central impor-

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