Insulin/IGF-1 Controls Epidermal Morphogenesis via Regulation of FoxO-Mediated p63 Inhibition

Abstract

SummaryThe multilayered epidermis is established through a stratification program, which is accompanied by a shift from symmetric toward asymmetric divisions (ACD), a process under tight control of the transcription factor p63. However, the physiological signals regulating p63 activity in epidermal morphogenesis remain ill defined. Here, we reveal a role for insulin/IGF-1 signaling (IIS) in the regulation of p63 activity. Loss of epidermal IIS leads to a biased loss of ACD, resulting in impaired stratification. Upon loss of IIS, FoxO transcription factors are retained in the nucleus, where they bind and inhibit p63-regulated transcription. This is reversed by small interfering RNA-mediated knockdown of FoxOs. Accordingly, transgenic expression of a constitutive nuclear FoxO variant in the epidermis abrogates ACD and inhibits p63-regulated transcription and stratification. Collectively, the present study reveals a critical role for IIS-dependent control of p63 activity in coordination of ACD and stratification during epithelial morphogenesis.

mTORC1 and mTORC2 regulate skin morphogenesis and epidermal barrier formation

“…Consistently, mTOR EKO epidermis also showed reduced expression of Irf6, Gata3 and Ikkα, and upregulated expression of Runx2, which represent activated or repressed targets by p63, respectively, that are critical in epidermal morphogenesis (Supplementary Fig. 2c)39404142.…”

PDK1 Is a Regulator of Epidermal Differentiation that Activates and Organizes Asymmetric Cell Division

“…In PDK1 deficient keratinocytes, phosphorylation of AKT, GSK3β and aPKC was reduced or completely abolished (Figure 4C). Insulin and insulin-like growth factor (IGF)-1 signaling has been implicated ACD, and mice lacking insulin and IGF-1 receptors exhibit a phenotype similar to the PDK1 CKO mice (Gunschmann et al, 2013). Consistent with the known role of PDK1, IGF-1 and epidermal growth factor (EGF) -induced phosphorylation of AKT and GSK3β was also completely abolished in PDK1 deficient keratinocytes (Figures S3E and F).…”

Sirtuins and their interactions with transcription factors and poly(ADP-ribose) polymerases

“…FOXO3 and FOXO4 are also deacetylated by SIRT1 and 2; this exerts a complex influence on their downstream mediators including superoxide dismutase, p27 kip1 , and GADD45 (growth arrest and DNA damage 45) and target processes such as stress resistance cell cycle and death [25,78,101,173,207] C SIRT1 enhances IIS signalling -it occurs through at least two ways: -deacetylation of p53 leads to reduction of its protein levels, relieving IIS inhibition by the IGF-binding protein-3 [215]; -SIRT1 can also directly deacetylate Akt, restoring its ability to bind phosphoinositides and become activated by phosphoinositide-dependent protein kinase 1 [192]). These dependencies have already been confirmed to impact metabolic deregulation, cardiac dysfunctions and tumour formation, and might result in inhibition of the IIS target FOXO1 [67]. In addition to SIRT1, also SIRT2 can physically interact with Akt; the sirtuins may be exchanged depending on the activation state of the IIS pathways.…”