c-Jun Is Essential for Organization of the Epidermal Leading Edge

Abstract

The migration of epithelial layers requires specific and coordinated organization of the cells at the leading edge of the sheet. Mice that are conditionally deleted for the c-jun protooncogene in epidermis are born at expected frequencies, but with open eyes and with defects in epidermal wound healing. Keratinocytes lacking c-Jun are unable to migrate or elongate properly in culture at the border of scratch assays. Histological analyses in vitro and in vivo demonstrate an inability to activate EGF receptor at the leading edge of wounds, and we demonstrate that this can be rescued by supplementation with conditioned medium or the EGF receptor ligand HB-EGF. Lack of c-Jun prevents EGF-induced expression of HB-EGF, indicating that c-jun controls formation of the epidermal leading edge through its control of an EGF receptor autocrine loop.

The Nuclear Hormone Receptor Coactivator NRC Is a Pleiotropic Modulator Affecting Growth, Development, Apoptosis, Reproduction, and Wound Repair

“…For example, NRC is a potent coregulator of c-Jun activity, which plays an important role in regulating genes involved in wound healing (integrins, laminins, and extracellular matrix genes in the epithelium) (1). In addition, c-Jun has recently been shown to stimulate expression of heparin-binding (HB) EGF in the basal layer of wounded epithelium, which in turn stimulates signaling by EGF receptor to regulate motility through regulation of focal adhesion kinase (38). The results obtained with skin explants from wild-type and NRC ϩ/Ϫ pups revealed a defect in migration of keratinocytes from NRC ϩ/Ϫ explants (Fig.…”

c-Jun, at the crossroad of the signaling network

“…Besides MAP3K1, embryonic eyelid closure depends on signals derived from WNT, Sonic hedgehog, BMP/Activin, FGF and EGF (Luetteke et al, 1993;Mine et al, 2005;Gage et al, 2008;Huang et al, 2009). In addition, eyelid closure requires the participation of a number of intracellular signaling kinases, such as JNK, ROCK and CDH1, and nuclear transcription factors, such as c-Jun, Fra-2, FOXL2, SMAD and GRHL3 (McHenry et al, 1998;Li et al, 2003;Zenz et al, 2003;Zhang et al, 2003;Uda et al, 2004;Thumkeo et al, 2005;Takatori et al, 2008;Yu et al, 2008;Naoe et al, 2010). While how these factors are organized into a morphogenetic network for eyelid closure has not been well understood, molecular analyses of these mice have begun to unveil that some of the factors are organized into concerted signal transduction cascades.…”

“…On the other hand, ablation of c-Jun specifically in keratinocytes does not affect skin development, but it causes EOB (Li et al, 2003;Zenz et al, 2003). It has been proposed that c-Jun regulates the expression of EGFR or its ligand HB-EGF, which are necessary for stimulating epithelial cell migration and embryonic eyelid closure (Grose, 2003).…”

Transcriptional control of epidermal specification and differentiation

“…Targeted ablations of individual AP-2 and AP-1 family members have failed to elucidate any specific role for a factor in skin development and differentiation, either because of an earlier embryonic lethality or potential functional redundancy. Mice with epidermal specific targeted ablation of AP-1 family member c-Jun show defects in EGF signaling [40,41]. The c-Jun null epidermis was unremarkable but insights came from culturing primary keratinocytes, which showed reduced proliferation and altered differentiation caused by the loss of paracrine factors provided by adjacent dermal cells of skin [40].…”