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A re-examination of proximodistal patterning during vertebrate limb development

Nature volume 418, pages 539–544 (2002)Cite this article

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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References

  1. Summerbell, D., Lewis, J. H. & Wolpert, L. Positional information in chick limb morphogenesis. Nature 244, 492–496 (1973)

    Article  ADS  CAS  Google Scholar 

  2. Rubin, L. & Saunders, J. W. Ectodermal-mesoderal interactions in the growth of limb buds in the chick embryo: constancy and temporal limits of ectodermal induction. Dev. Biol. 28, 94–112 (1972)

    Article  CAS  Google Scholar 

  3. Saunders, J. W. The proximo-distal sequence of origin of the parts of the chick wing and the role of the ectoderm. J. Exp. Zool. 108, 363–403 (1948)

    Article  Google Scholar 

  4. Summerbell, D. A quantitative analysis of the effect of excision of the AER from the chick limb-bud. J. Embryol. Exp. Morphol. 32, 651–660 (1974)

    CAS  PubMed  Google Scholar 

  5. Rowe, D. A., Cairns, J. M. & Fallon, J. F. Spatial and temporal patterns of cell death in limb bud mesoderm after apical ectodermal ridge removal. Dev. Biol. 93, 83–91 (1982)

    Article  CAS  Google Scholar 

  6. Niswander, L., Tickle, C., Vogel, A., Booth, I. & Martin, G. R. FGF-4 replaces the apical ectodermal ridge and directs outgrowth and patterning of the limb. Cell (1993)

  7. Fallon, J. F. et al. FGF-2: apical ectodermal ridge growth signal for chick limb development. Science 264, 104–107 (1994)

    Article  ADS  CAS  Google Scholar 

  8. Lewis, J. H. Fate maps and the pattern of cell division: a calculation for the chick wing bud. J. Embryol. Exp. Morphol. 33, 419–434 (1975)

    CAS  PubMed  Google Scholar 

  9. Sun, X., Mariani, F. V. & Martin, G. R. Functions of FGF signalling from the apical ectodermal ridge in limb development. Nature 418, 501–509 (2002)

    Article  ADS  CAS  Google Scholar 

  10. Vargesson, N., Clarke, J. D. W., Coles, V. K., Wolpert, L. & Tickle, C. Cell fate in the chick limb bud and relationship to gene expression. Development 124, 1909–1918 (1997)

    CAS  PubMed  Google Scholar 

  11. Gibson-Brown, J. J. et al. Evidence of a role for T-box genes in the evolution of limb morphogenesis and the specification of forelimb/hindlimb identity. Mech. Dev. 56, 93–101 (1996)

    Article  CAS  Google Scholar 

  12. Chapman, D. L. et al. Expression of the T-box family genes, Tbx1-Tbx5, during early mouse development. Dev. Dyn. 206, 379–390 (1996)

    Article  CAS  Google Scholar 

  13. Yokouchi, Y. et al. Misexpression of Hoxa-13 induces cartilage homeotic transformation and changes cell adhesiveness in chick limb buds. Genes Dev. 9, 2509–2522 (1995)

    Article  CAS  Google Scholar 

  14. Ros, M. A., Lyons, G. E., Mackem, S. & Fallon, J. F. Recombinant limbs as a model to study homeobox gene regulation during limb development. Dev. Biol. 166, 59–72 (1994)

    Article  CAS  Google Scholar 

  15. Wada, N., Ohsugi, K., Yokouchi, Y., Kuroiwa, A. & Ide, H. Cell sorting and chondrogenesis aggregate formation in limb bud recombinants and in culture. Dev. Growth Diff. 35, 421–430 (1998)

    Article  Google Scholar 

  16. Hardy, A. et al. Gene expression, polarising activity and skeletal patterning in reaggregated hind limb mesenchyme. Development 121, 4329–4337 (1995)

    CAS  PubMed  Google Scholar 

  17. Crosby, G. M. & Fallon, J. F. Inhibitory effect on limb morphogenesis by cells of the polarizing zone coaggregated with pre- or postaxial wing bud mesoderm. Dev. Biol. 46, 28–39 (1975)

    Article  CAS  Google Scholar 

  18. Frederick, J. M. & Fallon, J. F. The proportion and distribution of polarizing zone cells causing morphogenetic inhibition when coaggregated with anterior half wing mesoderm in recombinant limbs. J. Embryol. Exp. Morphol. 67, 13–25 (1982)

    Google Scholar 

  19. Piedra, M. E., Rivero, F. B., Fernandez-Teran, M. & Ros, M. A. Pattern formation and regulation of gene expressions in chick recombinant limbs. Mech. Dev. 90, 167–179 (2000)

    Article  Google Scholar 

  20. Wolpert, L., Tickle, C. & Sampford, M. The effect of cell killing by X-irradiation on pattern formation in the chick limb. J. Embryol. Exp. Morphol. 50, 175–198 (1979)

    CAS  PubMed  Google Scholar 

  21. Hornbruch, A. & Wolpert, L. Cell division in the early growth and morphogenesis of the chick limb. Nature 226, 764–766 (1970)

    Article  ADS  CAS  Google Scholar 

  22. Logan, M. & Tabin, C. Targeted gene misexpression in chick limb buds using avian replication-competent retroviruses. Methods 14, 407–420 (1998)

    Article  CAS  Google Scholar 

  23. Hamburger, V. & Hamilton, H. L. A series of normal stages in the development of the chick embryo. J. Morphol. 88, 49–92 (1951)

    Article  CAS  Google Scholar 

  24. Kieny, M. & Pautou, M.-P. Proximo-distal pattern regulation in deficient avian limb buds. Wilhelm Roux Arch. 183, 177–191 (1977)

    Article  Google Scholar 

  25. Gavrieli, Y., Sherman, Y. & Ben-Sasson, S. A. Identification of programmed cell death in situ via specific labeling of nuclear DNA fragmentation. J. Cell Biol. 119, 493–501 (1992)

    Article  CAS  Google Scholar 

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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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Authors and Affiliations

  1. Department of Genetics, Harvard Medical School, 200 Longwood Avenue, Boston, Massachusetts, 02115, USA

    Andrew T. Dudley & Clifford J. Tabin

  2. Departamento de Anatomía y Biología Celular, Facultad de Medicina, Universidad de Cantabria, Santander, 39011, Espana

    María A. Ros

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  1. Andrew T. Dudley
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  2. María A. Ros
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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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