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p63 is essential for regenerative proliferation in limb, craniofacial and epithelial development

Nature volume 398, pages 714–718 (1999)Cite this article

Abstract

The p63 gene, a homologue of the tumour-suppressor p53 (1–5), is highly expressed in the basal or progenitor layers of many epithelial tissues1. Here we report that mice homozygous for a disrupted p63 gene have major defects in their limb, craniofacial and epithelial development. p63 is expressed in the ectodermal surfaces of the limb buds, branchial arches and epidermal appendages, which are all sites of reciprocal signalling that direct morphogenetic patterning of the underlying mesoderm. The limb truncations are due to a failure to maintain the apical ectodermal ridge, a stratified epithelium, essential for limb development. The embryonic epidermis of p63 −/− mice undergoes an unusual process of non-regenerative differentiation, culminating in a striking absence of all squamous epithelia and their derivatives, including mammary, lacrymal and salivary glands. Taken together, our results indicate that p63 is critical for maintaining the progenitor-cell populations that are necessary to sustain epithelial development and morphogenesis.

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Figure 1: Disruption of the p63 gene in mice.
Figure 2: Defective limb development in p63−/− mice.
Figure 3: Defects in stratified epithelial differentiation in p63-deficient mice.
Figure 4: Expression of differentiation markers in p63−/− epidermis.
Figure 5: Model for p63 in maintaining the proliferative capacity of epithelial progenitor cells.

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Acknowledgements

We thank H. Green, M. Kirschner, P. Dotto, B. Olsen, N. Fukai, T. Rapoport, B.Quade, J. Glickman, P. Ferrara and T. Bestor for their support and for discussion; H. Green, G. Martin, A. McMahon, R. Johnson, A. Joyner and P. Dotto for reagents; L. Du for blastocyst injections; H. Liu for the 129 mouse genomic library; and J. Williams for histology preparations. This work was supported by grants from the NIH to R.B., C.T., A.S. and F.M.

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Authors and Affiliations

  1. Departments of Cell Biology,

    Annie Yang & Frank McKeon

  2. Genetics, Harvard Medical School,,

    Ronen Schweitzer & Cliff Tabin

  3. Immunology Research Division,

    Arlene Sharpe

  4. Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, 02115, Massachusetts, USA

    Deqin Sun, Arlene Sharpe & Christopher Crum

  5. Sanofi Biorecherche,, Innopole BP 137, Labege Cedex, 31676, France

    Mourad Kaghad, Nancy Walker & Daniel Caput

  6. US Department of Agriculture, and Department of Pathology, Human Nutrition Research Center on Aging, Tufts University School of Veterinary Medicine, Boston, 02111, Massachusetts, USA

    Roderick T. Bronson

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  1. Annie Yang
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Correspondence to Frank McKeon.

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Yang, A., Schweitzer, R., Sun, D. et al. p63 is essential for regenerative proliferation in limb, craniofacial and epithelial development. Nature 398, 714–718 (1999). https://doi.org/10.1038/19539

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