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.

Insulin receptor and cancer

“…In human embryonic stem (ES) cells, self-renewal and pluripotency depend on IGF2 production by human-ES cellderived fibroblast-like cells that act as a supportive niche (Bendall et al 2007). Other research groups have confirmed the important role of IGFs for a variety of stem/progenitor cells (McDevitt et al 2005, Yan et al 2006, Stachelscheid et al 2008. Interestingly, cord levels of IGFs in the newborn are positively associated with the total number of stem cells and with future cancer risk (Savarese et al 2007).…”

IGF signaling directs ventricular cardiomyocyte proliferation during embryonic heart development

“…All mouse lines used in this study have been described previously: conditional Igf1r/Insr mice (Stachelscheid et al, 2008), Igf2 -/+ (DeChiara et al, 1990), MLC2vCre (Chen et al, 1998) and Nkx2.5Cre (Moses et al, 2001). The Igf2 allele was maintained on a 129JS2 background; all other lines were on mixed and unspecified strain backgrounds.…”

Insulin receptor signaling mediates APP processing and β-amyloid accumulation without altering survival in a transgenic mouse model of Alzheimer’s disease

“…Due to this approach, we obtained in all four intercrossed strains (nIR −/− , nIGF-1R +/− , FoxO1ADA, and FoxO1DN) similar mortality rates of Tg2576 mice as described in the literature avoiding excessive mortality (El Khoury et al 2007;Matsubara et al 2003;Nathan et al 2005). IGF-1R lox/+ and IR lox/lox mice were generated and genotyped as described previously (Bruning et al 2000;Stachelscheid et al 2008) and crossed with synapsin-Cre (Syn-Cre) mice to achieve neuronspecific deletion. Mice which did not express APP SW or Syn-Cre served as controls.…”