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The Nuclear Hormone Receptor Peroxisome Proliferator-Activated Receptor ß/ Potentiates Cell Chemotactism, Polarization, and Migration ^,

Nguan Soon Tan, Guillaume Icre, Alexandra Montagner, Béatrice Bordier-ten Heggeler, Walter Wahli, and Liliane Michalik^*

Center for Integrative Genomics, National Research Center Frontiers in Genetics, University of Lausanne, CH-1015 Lausanne, Switzerland

Received 14 March 2007/ Returned for modification 17 April 2007/ Accepted 17 July 2007

After an injury, keratinocytes acquire the plasticity necessary for the reepithelialization of the wound. Here, we identify a novel pathway by which a nuclear hormone receptor, until now better known for its metabolic functions, potentiates cell migration. We show that peroxisome proliferator-activated receptor ß/ (PPARß/) enhances two phosphatidylinositol 3-kinase-dependent pathways, namely, the Akt and the Rho-GTPase pathways. This PPARß/ activity amplifies the response of keratinocytes to a chemotactic signal, promotes integrin recycling and remodeling of the actin cytoskeleton, and thereby favors cell migration. Using three-dimensional wound reconstructions, we demonstrate that these defects have a strong impact on in vivo skin healing, since PPARß/^–/– mice show an unexpected and rare epithelialization phenotype. Our findings demonstrate that nuclear hormone receptors not only regulate intercellular communication at the organism level but also participate in cell responses to a chemotactic signal. The implications of our findings may be far-reaching, considering that the mechanisms described here are important in many physiological and pathological situations.

Published ahead of print on 6 August 2007.

Supplemental material for this article may be found at http://mcb.asm.org/.

Present address: School of Biological Sciences, College of Sciences, Nanyang Technological University, 60 Nanyang Drive, Singapore 673551, Singapore.