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JCS ePress
online publication date 27 Mar 2007
doi: 10.1242/jcs.03426
Research Article
Impaired epidermal wound healing in vivo upon inhibition or deletion of Rac1
Michael Tscharntke,
Ruth Pofahl,
Anna Chrostek-Grashoff,
Neil Smyth,
Carien Niessen,
Catherin Niemann,
Benedikt Hartwig,
Volker Herzog,
Helmut W. Klein,
Thomas Krieg,
Cord Brakebusch,
and
Ingo Haase*
* Author for correspondence (e-mail: Ingo.Haase{at}uni-koeln.de)
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.
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© The Company of Biologists Ltd 2007
