Article
- The EMBO Journal (2008) 27, 2091 - 2101
- doi:10.1038/emboj.2008.141
Published online: 24 July 2008
Subject Categories:
Epidermal insulin/IGF-1 signalling control interfollicular morphogenesis and proliferative potential through Rac activation
Heike Stachelscheid1,2,a, Hady Ibrahim1,3,a, Linda Koch2,a, Annika Schmitz1,3, Michael Tscharntke3, F Thomas Wunderlich1, Jeanie Scott1,3, Christian Michels1,3, Claudia Wickenhauser4, Ingo Haase3, Jens C Brüning1,2,5 and Carien M Niessen1,3,5
- Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany
- Institute for Genetics, University of Cologne, Cologne, Germany
- Department of Dermatology, University of Cologne, Cologne, Germany
- Institute of Pathology, University of Cologne, Cologne, Germany
- Cologne Excellence Cluster on Cellular Stress Responses in Aging-associated Diseases (CECAD), University of Cologne, Cologne, Germany
Correspondence to:
Jens C Brüning, Institute for Genetics, University of Cologne, Zülpicherstrasse 47, 50674 Cologne, Germany. Tel.: +49 221 470 2467; Fax: +49 221 470 5185; E-mail: Jens.bruening@uni-koeln.de
Carien M Niessen, Center for Molecular Medicine Cologne, University of Cologne, Joseph Stelzmannstrasse 9, 50931 Cologne, Germany. Tel.: +49 221 478 7738; Fax: +49 221 478 4836; E-mail: carien.niessen@uni-koeln.de
aThese authors contributed equally to this work
Received 3 January 2008; Accepted 26 June 2008
Abstract
The lifelong self-renewal of the epidermis is driven by a progenitor cell population with high proliferative potential. To date, the upstream signals that determine this potential have remained largely elusive. Here, we find that insulin and insulin-like growth factor receptors (IR and IGF-1R) determine epidermal proliferative potential and cooperatively regulate interfollicular epidermal morphogenesis in a cell autonomous manner. Epidermal deletion of either IR or IGF-1R or both in mice progressively decreased epidermal thickness without affecting differentiation or apoptosis. Proliferation was temporarily reduced at E17.5 in the absence of IGF-1R but not IR. In contrast, clonogenic capacity was impaired in both IR- and IGF-1R-deficient primary keratinocytes, concomitant with an in vivo loss of keratin 15. Together with a reduction in label-retaining cells in the interfollicular epidermis, this suggests that IR/IGF-1R regulate progenitor cells. The expression of dominant active Rac rescued clonogenic potential of IR/IGF-1R-negative keratinocytes and reversed epidermal thinning in vivo. Our results identify the small GTPase Rac as a key target of epidermal IR/IGF-1R signalling crucial for proliferative potential and interfollicular morphogenesis.
Keywords:
- IGF-1 receptor,
- insulin,
- interfollicular progenitor cells,
- K14-Cre,
- transgenic mice
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