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c-Jun is essential for organization of the epidermal leading edge
Guochun Li1, Cindy Gustafson-Brown, Steven K Hanks
1Molecular Biology Section, Division of Biological Sciences, University of California, San Diego, La Jolla, CA 92093, USA.
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.
Insights
The c-Jun protooncogene is crucial for skin healing. Its absence impairs keratinocyte migration and epidermal wound repair by disrupting an EGF receptor signaling loop.
Area of Science:
- * Molecular biology
- * Cell biology
- * Dermatology
Background:
- * Epithelial cell migration is vital for tissue repair and development.
- * The c-Jun protooncogene plays a role in cellular processes.
- * Epidermal wound healing requires coordinated cell movement at the leading edge.
Purpose of the Study:
- * To investigate the role of c-Jun in epidermal wound healing.
- * To understand the molecular mechanisms underlying c-Jun's function in keratinocyte migration.
- * To identify how c-Jun regulates the leading edge organization during epithelial repair.
Main Methods:
- * Conditional deletion of the c-Jun protooncogene in mouse epidermis.
- * In vitro scratch assays using cultured keratinocytes lacking c-Jun.
- * Histological analyses of skin wounds in vivo and in vitro.
- * Assessment of EGF receptor activation and HB-EGF expression.
Main Results:
- * Mice lacking c-Jun in the epidermis exhibit open eyes and impaired wound healing.
- * c-Jun-deficient keratinocytes show defective migration and elongation in scratch assays.
- * The leading edge of wounds in c-Jun deficient mice fails to activate the EGF receptor.
- * Supplementation with conditioned medium or HB-EGF rescues the migratory defect.
- * c-Jun is required for EGF-induced HB-EGF expression.
Conclusions:
- * c-Jun is essential for proper epidermal wound healing and keratinocyte migration.
- * The c-Jun protooncogene controls the formation of the epidermal leading edge.
- * c-Jun regulates an autocrine loop involving the EGF receptor and HB-EGF.
- * Disruption of this c-Jun-dependent signaling pathway leads to impaired wound repair.