Epidermal insulin/IGF-1 Signalling Control Interfollicular Morphogenesis and Proliferative Potential Through Rac Activation

EMBO J. 2008 Aug 6;27(15):2091-101. doi: 10.1038/emboj.2008.141. Epub 2008 Jul 24.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Animals, Newborn
  • Apoptosis / physiology
  • Cell Differentiation
  • Cell Proliferation*
  • Cells, Cultured
  • Epidermal Cells
  • Epidermis / embryology
  • Epidermis / physiology*
  • Insulin / metabolism
  • Insulin-Like Growth Factor I / metabolism
  • Keratin-15 / metabolism
  • Keratinocytes / cytology
  • Keratinocytes / physiology
  • Mesenchymal Stem Cells / cytology
  • Mesenchymal Stem Cells / physiology
  • Mice
  • Morphogenesis
  • Receptor, IGF Type 1 / physiology*
  • Receptor, Insulin / physiology*
  • Signal Transduction
  • rac GTP-Binding Proteins / physiology*

Substances

  • Insulin
  • Keratin-15
  • Krt15 protein, mouse
  • Insulin-Like Growth Factor I
  • Receptor, IGF Type 1
  • Receptor, Insulin
  • rac GTP-Binding Proteins