The nuclear hormone receptor peroxisome proliferator-activated receptor beta/delta potentiates cell chemotactism, polarization, and migration.
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 beta/delta (PPARbeta/delta) enhances two phosphatidylinositol 3-kinase-dependent pathways, namely, the Akt and the Rho-GTPase pathways. This PPARbeta/delta 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 PPARbeta/delta-/- 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.
Center for Integrative Genomics, National Research Center Frontiers in Genetics, University of Lausanne, CH-1015 Lausanne, Switzerland.
Nguan Soon
NS
Tan
Guillaume
G
Icre
Alexandra
A
Montagner
Béatrice
B
Bordier-ten-Heggeler
Walter
W
Wahli
Liliane
L
Michalik
D000199:Actins / Q000378:metabolism; D000818:Animals; D002465:Cell Movement / Q000502:physiology*; D016764:Cell Polarity; D002478:Cells, Cultured; D002633:Chemotaxis / Q000502:physiology*; D004789:Enzyme Activation; D004815:Epidermal Growth Factor / Q000378:metabolism; D006801:Humans; D015603:Keratinocytes / Q000166:cytology / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D047494:PPAR delta / Q000235:genetics / Q000378:metabolism*; D048068:PPAR-beta / Q000235:genetics / Q000378:metabolism*; D010641:Phenotype; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D022502:Stress Fibers / Q000378:metabolism; D014945:Wound Healing; D020764:cdc42 GTP-Binding Protein / Q000378:metabolism; D020830:rac1 GTP-Binding Protein / Q000378:metabolism; D020741:rho GTP-Binding Proteins / Q000378:metabolism
D000199:Actins; D047494:PPAR delta; D048068:PPAR-beta; D004815:Epidermal Growth Factor; D019869:Phosphatidylinositol 3-Kinases; C514862:Akt1 protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D020764:cdc42 GTP-Binding Protein; D020830:rac1 GTP-Binding Protein; D020741:rho GTP-Binding Proteins