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The 'progress zone' model of limb development posits that the embryonic cells that become limbs are specified in a progressive manner: first, the upper part; then the middle; and last, hand or foot. Despite there being no direct evidence for this, the model remained unquestioned for more than 25 years. Then, in 2002, it was challenged by new observations, and an 'early specification' model was proposed, which suggested that progenitor cells forming each segment of a limb are specified all at once, early in development. On page 401, Gail Martin, a developmental biologist at the University of California, San Francisco, and her colleagues revise the early specification model.

What cast doubt on the progress zone model?

The model was based on observations that removing the apical ectodermal ridge — the cells rimming the tip of the limb bud — early in development stopped limb formation at the upper arm, and that later removal stopped it at the wrist. But, in 2002, Cliff Tabin's group at Harvard Medical School showed that ridge removal kills underlying progenitor cells that are required for limb formation, and went on to propose the early specification model. At the same time, my group showed that removal of signalling molecules called fibroblast growth factors (FGFs) from the ridge yielded limbs with hand elements even though a middle element was missing — findings not readily explained by the progress zone model.

Does your current work debunk the progress zone model?

No. The study shows that FGFs from the ridge instruct progenitor cells what part of the limb to form; the progress zone model assumed that the ridge only permitted development rather than instructing it. We carried out a genetic analysis, using a series of limb buds in which FGF signals were progressively reduced. Our results suggest that two signals — one, FGF, from the limb-bud tip and another presumably from the limb-bud base — are integrated in a dynamic process to specify the different limb segments.

What do you need to test the models?

We need to identify molecular markers that report specification of the progenitors for the different limb segments as soon as it occurs.

You discovered embryonic stem cells. Does medical usefulness drive your research?

No. I'm interested in basic biological processes. But I think that understanding how normal development is controlled is the most expeditious route to discovering therapies for many diseases.