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Skin abnormalities generated by temporally controlled RXRα mutations in mouse epidermis

Nature volume 407, pages 633–636 (2000)Cite this article

Abstract

Nuclear receptors for retinoids (RARs) and vitamin D (VDR), and for some other ligands (TRs, PPARs and LXRs), may be critical in the development and homeostasis of mammalian epidermis1,2,3,4,5,6,7,8. It is believed that these receptors form heterodimers with retinoid X receptors (RXRs) to act as transcriptional regulators9,10. However, most genetic approaches aimed at establishing their physiological functions in the skin have been inconclusive owing either to pleiotropic effects and redundancies between receptor isotypes in gene knockouts, or to equivocal interpretation of dominant-negative mutant studies in transgenic mice1,13,14,15. Moreover, knockout of RXRα, the main skin RXR isotype, is lethal in utero before skin formation11,12,16,17. Here we have resolved these problems by developing an efficient technique to create spatio-temporally controlled somatic mutations in the mouse. We used tamoxifen-inducible Cre–ERT recombinases18,19 to ablate RXRα selectively in adult mouse keratinocytes. We show that RXRα has key roles in hair cycling, probably through RXR/VDR heterodimers, and in epidermal keratinocyte proliferation and differentiation.

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Figure 1: Tamoxifen-induced RXRα null mutation in adult mouse epidermis mediated by Cre–ERT.
Figure 2: Abnormalities generated by Tam-induced disruption of RXRα in skin of adult mouse mediated by K5–Cre–ERT and K14–Cre–ERT2.
Figure 3: Comparison of skin abnormalities exhibited by a Tam-treated K5–Cre–ERT(tg/10) RXRαL2/L2/RXRβ-/- mouse and a VDR-null mouse.

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References

  1. Fisher, G. J. & Voorhees, J. J. Molecular mechanisms of retinoid actions in skin. FASEB J. 10, 1002– 1013 (1996).

    Article  CAS  Google Scholar 

  2. Yoshizawa, T. et al. Mice lacking the vitamin D receptor exhibit impaired bone formation, uterine hypoplasia and growth retardation after weaning. Nature Genet. 16, 391–396 (1997).

    Article  CAS  Google Scholar 

  3. Li, Y. C. et al. Targeted ablation of the vitamin D receptor: an animal model of vitamin D-dependent rickets type II with alopecia. Proc. Natl Acad. Sci. USA 94, 9831–9835 (1997).

    Article  ADS  CAS  Google Scholar 

  4. Li, Y. C. et al. Normalization of mineral ion homeostasis by dietary means prevents hyperparathyroidism, rickets, and osteomalacia, but not alopecia in vitamin D receptor-ablated mice. Endocrinology 139, 4391–4396 (1998).

    Article  CAS  Google Scholar 

  5. Kömüves, L. G. et al. Ligands and activators of nuclear hormone receptors regulate epidermal differentiation during fetal rat skin development. J. Invest. Dermatol. 111, 429–433 (1998).

    Article  Google Scholar 

  6. Hanley, K. et al. Activators of the nuclear hormone receptors PPARα and FXR accelerate the development of the fetal epidermal permeability barrier. J. Clin. Invest. 100, 705–712 (1997).

    Article  CAS  Google Scholar 

  7. Hanley, K. et al. Oxysterols induce differentiation in human keratinocytes and increase Ap-1-dependent involucrin transcription. J. Invest. Dermatol. 114, 545–553 ( 2000).

    Article  CAS  Google Scholar 

  8. Hanley, K. et al. Farnesol stimulates differentiation in epidermal keratinocytes via PPARα. J. Biol. Chem. 275, 11484 –11491 (2000).

    Article  CAS  Google Scholar 

  9. Mangelsdorf, D. J. et al. The nuclear receptor superfamily: the second decade. Cell 83, 835–839 ( 1995).

    Article  CAS  Google Scholar 

  10. Chambon, P. A decade of molecular biology of retinoic acid receptors. FASEB J. 10, 940–954 ( 1996).

    Article  CAS  Google Scholar 

  11. Kastner, P., Mark, M. & Chambon, P. Nonsteroid nuclear receptors: what are genetic studies telling us about their role in real life? Cell 83, 859–869 (1995).

    Article  CAS  Google Scholar 

  12. Mascrez, B. et al. The RXRα ligand-dependent activation function 2 (AF-2) is important for mouse development. Development 125 , 4691–4707 (1998).

    CAS  PubMed  Google Scholar 

  13. Saitou, M. et al. Inhibition of skin development by targeted expression of a dominant-negative retinoic acid receptor. Nature 374 , 159–162 (1995).

    Article  ADS  CAS  Google Scholar 

  14. Imakado, S. et al. Targeting expression of a dominant-negative retinoic acid receptor mutant in the epidermis of transgenic mice results in loss of barrier function. Genes Dev. 9, 317– 329 (1995).

    Article  CAS  Google Scholar 

  15. Feng, X. et al. Suprabasal expression of a dominant-negative RXRα mutant in transgenic mouse epidermis impairs regulation of gene transcription and basal keratinocyte proliferation by RAR-selective retinoids. Genes Dev. 11, 59–71 ( 1997).

    Article  CAS  Google Scholar 

  16. Kastner, P. et al. Genetic analysis of RXRα developmental function: convergence of RXR and RAR signalling pathways in heart and eye morphogenesis. Cell 78, 987–1003 ( 1994).

    Article  CAS  Google Scholar 

  17. Sucov, H. M. et al. RXR alpha mutant mice establish a genetic basis for vitamin A signaling in heart morphogenesis. Genes Dev. 8, 1007–1018 (1994).

    Article  CAS  Google Scholar 

  18. Metzger, D. & Chambon, P. Site- and time-specific gene targeting in the mouse. Methods (in the press).

  19. Indra, A. K. et al. Temporally-controlled site-specific mutagenesis in the basal layer of the epidermis: comparison of the recombinase activity of the tamoxifen-inducible Cre-ERT and Cre-ERT2 recombinases. Nucleic Acids Res. 27, 4324–4327 (1999).

    Article  CAS  Google Scholar 

  20. Sundberg, J. P. & King, L. E. Mouse models for the study of human hair loss. Dermatol. Clin. 14, 619–632 (1996).

    Article  CAS  Google Scholar 

  21. Panteleyev, A. A., Paus, R., Ahmad, W., Sundberg, J. P. & Christiano, A. M. Molecular and functional aspects of the hairless (hr) gene in laboratory rodents and humans. Exp. Dermatol. 7, 249–267 (1998).

    Article  CAS  Google Scholar 

  22. Porter, R. M., Reichelt, J., Lunny, D. P., Magin, T. M. & Lane, B. The relationship between hyperproliferation and epidermal thickening in a mouse model for BCIE. J. Invest. Dermatol. 110, 951–957 ( 1998).

    Article  CAS  Google Scholar 

  23. Vassar, R., Rosenberg, M., Ross, S., Tyner, A. & Fuchs, E. Tissue-specific and differentiation-specific expression of a human K14 keratin gene in transgenic mice. Proc. Natl Acad. Sci. USA 86, 1563–1567 ( 1989).

    Article  ADS  CAS  Google Scholar 

  24. Wang, X., Zinkel, S., Polonsky, K. & Fuchs, E. Transgenic studies with a keratin promoter-driven growth hormone transgene: prospects for gene therapy. Proc. Natl Acad. Sci. USA 94, 219 –226 (1997).

    Article  ADS  CAS  Google Scholar 

  25. Kastner, P. et al. Abnormal spermatogenesis in RXRβ mutant mice. Genes Dev. 10, 80–92 ( 1996).

    Article  CAS  Google Scholar 

  26. Wendling, O., Chambon, P. & Mark, M. Retinoid X receptors are essential for early mouse development and placentogenesis. Proc. Natl Acad. Sci. USA 96, 547–551 (1999).

    Article  ADS  CAS  Google Scholar 

  27. Reichrath, J. et al. Hair follicle expression of 1,25-dihydroxyvitamin D3 receptors during the murine hair cycle. Br. J. Dermatol. 131, 477–482 (1994).

    Article  CAS  Google Scholar 

  28. Braissant, O., Foufelle, F., Scotto, C., Dauça, M. & Wahli, W. Differential expression of peroxisome proliferator-activated receptors (PPARs): tissue distribution of PPAR-α,-β, and-γ in the adult rat. Endocrinology 137, 354 –366 (1996).

    Article  CAS  Google Scholar 

  29. Metzger, D. et al. Conditional site-specific recombination in mammalian cells using a ligand-dependent chimeric Cre recombinase. Proc. Natl Acad. Sci. USA 92, 6991–6995 ( 1995).

    Article  ADS  CAS  Google Scholar 

  30. Brocard, J. et al. Spatio-temporally controlled site-specific somatic mutagenesis in the mouse. Proc. Natl Acad. Sci. USA 94, 14559–14563 (1997).

    Article  ADS  CAS  Google Scholar 

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Acknowledgements

We thank S. Werner for the human K14 promoter; H. Chiba and P. Kastner for RXRαL2/+, RXRα+/- and RXRβ+/-mice; J. M. Bornert, S. Bronner, N. Chartoire, M. Duval, C. Gérard, R. Lorentz and J. L. Vonesch for technical help; M. LeMeur, R. Matyas and the animal facility staff for animal care; M. Mark for histological analysis; the secretariat for typing the manuscript and the illustration staff for preparing the figures; and all the members of the laboratory for helpful discussions. This work was supported by funds from the Centre National de la Recherche Scientifique, the Institut National de la Santé et de la Recherche Médicale, the Collège de France, the Hôpital Universitaire de Strasbourg, the Association pour la Recherche sur le Cancer, the Fondation pour la Recherche Médicale, the Human Frontier Science Program, the Ministère de l’Éducation Nationale de la Recherche et de la Technologie and the European Economic Community. M.L. was supported by fellowships from the Association pour la Recherche sur le Cancer and the Fondation pour la Recherche Médicale, A.K.I. by a fellowship from the Université Louis Pasteur (Strasbourg), and J.B. and X.W. by fellowships from the Ministère de l’Education Nationale, de la Recherche et de la Technologie and from the Fondation pour la Recherche Médicale.

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Author notes

  1. Mei Li, Arup Kumar Indra and Shigeaki Kato: These authors contributed equally to this work

Authors and Affiliations

  1. Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS/INSERM/ULP, Collège de France, BP 163, Illkirch Cedex, 67404, France

    Mei Li, Arup Kumar Indra, Xavier Warot, Jacques Brocard, Nadia Messaddeq, Daniel Metzger & Pierre Chambon

  2. Institute of Molecular & Cellular Biosciences, University of Tokyo, Yayoi, Bunkyo-ku , 113, Tokyo, Japan

    Shigeaki Kato

  3. CREST, Japan Science and Technology , Kawaguchi, 332, Saitama, Japan

    Shigeaki Kato

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  1. Mei Li
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Correspondence to Pierre Chambon.

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Li, M., Indra, A., Warot, X. et al. Skin abnormalities generated by temporally controlled RXRα mutations in mouse epidermis. Nature 407, 633–636 (2000). https://doi.org/10.1038/35036595

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