title: Epidermal insulin/IGF-1 signalling control interfollicular morphogenesis and proliferative potential through Rac activation.
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.
authors.affiliation: Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany.
authors.forename: Heike
authors.initials: H
authors.lastname: Stachelscheid
authors.forename: Hady
authors.initials: H
authors.lastname: Ibrahim
authors.forename: Linda
authors.initials: L
authors.lastname: Koch
authors.forename: Annika
authors.initials: A
authors.lastname: Schmitz
authors.forename: Michael
authors.initials: M
authors.lastname: Tscharntke
authors.forename: F Thomas
authors.initials: FT
authors.lastname: Wunderlich
authors.forename: Jeanie
authors.initials: J
authors.lastname: Scott
authors.forename: Christian
authors.initials: C
authors.lastname: Michels
authors.forename: Claudia
authors.initials: C
authors.lastname: Wickenhauser
authors.forename: Ingo
authors.initials: I
authors.lastname: Haase
authors.forename: Jens C
authors.initials: JC
authors.lastname: Brüning
authors.forename: Carien M
authors.initials: CM
authors.lastname: Niessen
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis / Q000502:physiology; D002454:Cell Differentiation; D049109:Cell Proliferation; D002478:Cells, Cultured; D000078404:Epidermal Cells; D004817:Epidermis / Q000196:embryology / Q000502:physiology*; D007328:Insulin / Q000378:metabolism; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D053569:Keratin-15 / Q000378:metabolism; D015603:Keratinocytes / Q000166:cytology / Q000502:physiology; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000502:physiology; D051379:Mice; D009024:Morphogenesis; D017526:Receptor, IGF Type 1 / Q000502:physiology*; D011972:Receptor, Insulin / Q000502:physiology*; D015398:Signal Transduction; D020744:rac GTP-Binding Proteins / Q000502:physiology*
chemical_list: D007328:Insulin; D053569:Keratin-15; C492053:Krt15 protein, mouse; D007334:Insulin-Like Growth Factor I; D017526:Receptor, IGF Type 1; D011972:Receptor, Insulin; D020744:rac GTP-Binding Proteins