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First published online 27 March 2007
doi: 10.1242/jcs.03426

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Impaired epidermal wound healing in vivo upon inhibition or deletion of Rac1

¹ Department of Dermatology, University of Cologne and Center for Molecular Medicine, University of Cologne (CMMC), Joseph-Stelzmann-Strasse 9, 50924 Cologne, Germany
² Max Planck Institute of Biochemistry, Department of Molecular Medicine, Am Klopferspitz 18, 82152 Martinsried, Germany
³ University of Southampton, School of Biological Sciences, Bassett Crescent East, Southampton, SO16 7PX, UK
⁴ Department of Pathology, University of Cologne and Center for Molecular Medicine, University of Cologne (CMMC), Joseph-Stelzmann-Strasse 9, 50924 Cologne, Germany
⁵ Institute for Cell Biology, University of Bonn, Ulrich Haberlandstrasse 61a, 53121 Bonn, Germany
⁶ Institute of Biochemistry, University of Cologne, Otto Fischer-Strasse 12-14, 50674 Cologne, Germany
⁷ University of Kopenhagen, Institute of Molecular Pathology, Frederik V's Vej 11, 2100 Kopenhagen, Denmark

^* Author for correspondence (e-mail: Ingo.Haase{at}uni-koeln.de)

Accepted 8 February 2007

To address the functions of Rac1 in keratinocytes of the basal epidermal layer and in the outer root sheath of hair follicles, we generated transgenic mice expressing a dominant inhibitory mutant of Rac, N17Rac1, under the control of the keratin 14 promoter. These mice do not exhibit an overt skin phenotype but show protracted skin wound re-epithelialization. Investigation into the underlying mechanisms revealed that in vivo both proliferation of wound-edge keratinocytes and centripetal migration of the neo-epidermis were impaired. Similar results were obtained in mice with an epidermis-specific deletion of Rac1. Primary epidermal keratinocytes that expressed the N17Rac1 transgene were less proliferative than control cells and showed reduced ERK1/2 phosphorylation upon growth factor stimulation. Adhesion, spreading, random migration and closure of scratch wounds in vitro were significantly inhibited on collagen I and, to a lesser extent, on fibronectin. Stroboscopic analysis of cell dynamics (SACED) of N17Rac1 transgenic and control keratinocytes identified decreased lamella-protrusion persistence in connection with increased ruffle frequency as a probable mechanism for the observed impairment of keratinocyte adhesion and migration. We conclude that Rac1 is functionally required for normal epidermal wound healing and, in this context, exerts a dual function – namely the regulation of keratinocyte proliferation and migration.

Key words: Rac, Epidermis, Wound healing, Keratinocyte, Proliferation, Migration

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