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A re-examination of proximodistal patterning during vertebrate limb development

Abstract

The ‘progress zone’ model provides a framework for understanding progressive development of the vertebrate limb1. This model holds that undifferentiated cells in a zone of fixed size at the distal tip of the limb bud (the progress zone) undergo a progressive change in positional information such that their specification is altered from more proximal to more distal fates. This positional change is thought to be driven by an internal clock that is kept active as long as the cells remain in the progress zone. However, owing to cell division, the most proximal of these cells are continually pushed outside the confines of the zone. As they exit, clock function ceases and cells become fixed with the positional value last attained while within the zone. In contrast to this model, our data suggest that the various limb segments are ‘specified’ early in limb development as distinct domains, with subsequent development involving expansion of these progenitor populations before differentiation. We also find, however, that the distal limb mesenchyme becomes progressively ‘determined’, that is, irreversibly fixed, to a progressively limited range of potential proximodistal fates.

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Figure 1: Removal of the AER results in the onset of cell death and a decrease in cell proliferation in the distal mesenchyme.
Figure 2: Cell death and decreased cell proliferation are significant factors in phenotypes produced by AER removal.
Figure 3: Descendents of cells in the early limb bud contribute to only one proximodistal segment.
Figure 4: Distal cell fates are already specified but not determined in the early limb bud.

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Acknowledgements

We thank J. Fallon for discussions about cell death; C. Tickle, G. Martin and J. Saunders for critiques of our data; A. Brent, N. Davis, C. Hartmann, G. Kardon, G. Martin, R. Pearse and K. Vogan for critical reading of this manuscript; and G. Martin and X. Sun for sharing data before publication. This work was supported by a grant from the National Institutes of Health (C.J.T.) and a fellowship from the Leukemia and Lymphoma Society (A.T.D.). M.A.R. was funded by the Spanish Ministry of Education and Culture.

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Correspondence to Clifford J. Tabin.

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Dudley, A., Ros, M. & Tabin, C. A re-examination of proximodistal patterning during vertebrate limb development. Nature 418, 539–544 (2002). https://doi.org/10.1038/nature00945

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