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.