Epidermal insulin/IGF-1 signalling control interfollicular morphogenesis and proliferative potential through Rac activation.
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.
Stachelscheid
Heike
H
Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany.
Ibrahim
Hady
H
Koch
Linda
L
Schmitz
Annika
A
Tscharntke
Michael
M
Wunderlich
F Thomas
FT
Scott
Jeanie
J
Michels
Christian
C
Wickenhauser
Claudia
C
Haase
Ingo
I
Brüning
Jens C
JC
Niessen
Carien M
CM
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*
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