Impaired skin wound healing in peroxisome proliferator-activated receptor (PPAR){alpha} and PPAR{beta} mutant mice

doi:10.1083/jcb.200011148

Published 20 August 2001. doi:10.1083/jcb.200011148

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© The Rockefeller University Press, 0021-9525/2001/8/799 $5.00
The Journal of Cell Biology, Volume 154, Number 4, August 20, 2001 799-814

Article

Impaired skin wound healing in peroxisome proliferator–activated receptor (PPAR) ${alpha}$ and PPARß mutant mice

Liliane Michalik¹, Béatrice Desvergne¹, Nguan Soon Tan¹, Sharmila Basu-Modak¹, Pascal Escher¹, Jennifer Rieusset¹, Jeffrey M. Peters³, Gürkan Kaya², Frank J. Gonzalez³, Jozsef Zakany⁴, Daniel Metzger⁵, Pierre Chambon⁵, Denis Duboule⁴ and Walter Wahli¹

¹ Institut de Biologie Animale, Université de Lausanne, Bâtiment de Biologie, CH-1015 Lausanne, Switzerland
² Department of Dermatology, University Hospital of Geneva, CH-1212 Geneva, Switzerland
³ Laboratory of Molecular Carcinogenesis, National Cancer Institute, National Institute of Health, Bethesda, MD 20892
⁴ Département de Zoologie, Université de Genève, Sciences III, CH-1211 Geneva 4, Switzerland
⁵ Institut de Génétique et de Biologie Moléculaire et Cellulaire, Centre National de la Recherche Scientifique/Institut National de la Santé et de la Recherche Médicale/ULP/Collège de France, 67404 Illkirch Cedex, CU de Strasbourg, France

Address correspondence to Walter Wahli, Institut de Biologie Animale, Université de Lausanne, Bâtiment de Biologie, CH-1015 Lausanne, Switzerland. Tel.: (41) 21-692-41-10. Fax: (41) 21-692-41-15. E-mail: walter.wahli{at}iba.unil.ch

We show here that the ${alpha}$ , ß, and ${gamma}$ isotypes of peroxisomeproliferator–activated receptor (PPAR) are expressed inthe mouse epidermis during fetal development and that they disappearprogressively from the interfollicular epithelium after birth.Interestingly, PPAR ${alpha}$ and ß expression is reactivatedin the adult epidermis after various stimuli, resulting in keratinocyteproliferation and differentiation such as tetradecanoylphorbolacetate topical application, hair plucking, or skin wound healing.Using PPAR ${alpha}$ , ß, and ${gamma}$ mutant mice, we demonstrate thatPPAR ${alpha}$ and ß are important for the rapid epithelializationof a skin wound and that each of them plays a specific rolein this process. PPAR ${alpha}$ is mainly involved in the early inflammationphase of the healing, whereas PPARß is implicatedin the control of keratinocyte proliferation. In addition andvery interestingly, PPARß mutant primary keratinocytesshow impaired adhesion and migration properties. Thus, the findingspresented here reveal unpredicted roles for PPAR ${alpha}$ and ßin adult mouse epidermal repair.

Key Words: mouse keratinocytes; PPAR gene expression; PPAR gene targeted disruption; skin wound healing; nuclear hormone receptors

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