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

Impaired epidermal wound healing in vivo upon inhibition or deletion of Rac1
Impaired epidermal wound healing in vivo upon inhibition or deletion of Rac1
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.
rac, epidermis, wound healing, keratinocyte, proliferation, migration
0021-9533
1480-1490
Tscharntke, Michael
69c38548-b8b9-4b29-aacf-ebe7a6d3f29f
Pofahl, Ruth
fa34b84c-bed8-41d5-a171-3032c979beae
Chrostek-Grashoff, Anna
0b7e6461-57eb-4dde-b847-1283c05d27e9
Smyth, Neil
0eba2a40-3b43-4d40-bb64-621bd7e9d505
Niessen, Carien
126c85db-3ccd-40ac-835e-99670aba4115
Niemann, Catherin
d538f0d2-32e2-4d6d-90a6-c0367edff7f4
Hartwig, Benedikt
32e96c80-7444-404a-a852-e1a10c97914c
Herzog, Volker
68ed8d6a-621b-46e3-a960-d36168c98392
Klein, Helmut W.
67f88246-ad90-4192-aa8c-69a65a7f3fc6
Krieg, Thomas
91cd8b68-3120-4178-b2dd-0424a5fe43d0
Brakebusch, Cord
bd382b3b-16a8-4b19-85a4-38ebdc4f1bac
Haase, Ingo
ac79eb82-0dc5-4412-8073-785fb0244789
Tscharntke, Michael
69c38548-b8b9-4b29-aacf-ebe7a6d3f29f
Pofahl, Ruth
fa34b84c-bed8-41d5-a171-3032c979beae
Chrostek-Grashoff, Anna
0b7e6461-57eb-4dde-b847-1283c05d27e9
Smyth, Neil
0eba2a40-3b43-4d40-bb64-621bd7e9d505
Niessen, Carien
126c85db-3ccd-40ac-835e-99670aba4115
Niemann, Catherin
d538f0d2-32e2-4d6d-90a6-c0367edff7f4
Hartwig, Benedikt
32e96c80-7444-404a-a852-e1a10c97914c
Herzog, Volker
68ed8d6a-621b-46e3-a960-d36168c98392
Klein, Helmut W.
67f88246-ad90-4192-aa8c-69a65a7f3fc6
Krieg, Thomas
91cd8b68-3120-4178-b2dd-0424a5fe43d0
Brakebusch, Cord
bd382b3b-16a8-4b19-85a4-38ebdc4f1bac
Haase, Ingo
ac79eb82-0dc5-4412-8073-785fb0244789

Tscharntke, Michael, Pofahl, Ruth, Chrostek-Grashoff, Anna, Smyth, Neil, Niessen, Carien, Niemann, Catherin, Hartwig, Benedikt, Herzog, Volker, Klein, Helmut W., Krieg, Thomas, Brakebusch, Cord and Haase, Ingo (2007) Impaired epidermal wound healing in vivo upon inhibition or deletion of Rac1. Journal of Cell Science, 120 (8), 1480-1490. (doi:10.1242/jcs.03426).

Record type: Article

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.

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More information

Published date: 15 April 2007
Keywords: rac, epidermis, wound healing, keratinocyte, proliferation, migration

Identifiers

Local EPrints ID: 55922
URI: http://eprints.soton.ac.uk/id/eprint/55922
ISSN: 0021-9533
PURE UUID: 826ce647-84f5-4abd-be81-b45ca5e191b2

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Date deposited: 06 Aug 2008
Last modified: 15 Mar 2024 10:58

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Contributors

Author: Michael Tscharntke
Author: Ruth Pofahl
Author: Anna Chrostek-Grashoff
Author: Neil Smyth
Author: Carien Niessen
Author: Catherin Niemann
Author: Benedikt Hartwig
Author: Volker Herzog
Author: Helmut W. Klein
Author: Thomas Krieg
Author: Cord Brakebusch
Author: Ingo Haase

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