title: Impaired epidermal wound healing in vivo upon inhibition or deletion of Rac1.
abstract: 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.
authors: Department of Dermatology, University of Cologne, Center for Molecular Medicine, (CMMC), Joseph-Stelzmann-Strasse 9, 50924 Cologne, Germany.
authors: Michael
authors: M
authors: Tscharntke
authors: Ruth
authors: R
authors: Pofahl
authors: Anna
authors: A
authors: Chrostek-Grashoff
authors: Neil
authors: N
authors: Smyth
authors: Carien
authors: C
authors: Niessen
authors: Catherin
authors: C
authors: Niemann
authors: Benedikt
authors: B
authors: Hartwig
authors: Volker
authors: V
authors: Herzog
authors: Helmut W
authors: HW
authors: Klein
authors: Thomas
authors: T
authors: Krieg
authors: Cord
authors: C
authors: Brakebusch
authors: Ingo
authors: I
authors: Haase
mesh_terms: D000818:Animals; D002448:Cell Adhesion / Q000502:physiology; D002465:Cell Movement / Q000502:physiology; D049109:Cell Proliferation; D004817:Epidermis / Q000503:physiopathology*; D015603:Keratinocytes / Q000166:cytology; D014945:Wound Healing; D020830:rac1 GTP-Binding Protein / Q000235:genetics / Q000502:physiology*
chemical_list: C107953:RAC1 protein, human; D020830:rac1 GTP-Binding Protein