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NEDD4-1 is a key regulator of epidermal homeostasis and wound repair

  • Shen Yan
    Affiliations
    Institute of Molecular Health Sciences, Department of Biology, Swiss Federal Institute of Technology (ETH) Zurich, Otto-Stern-Weg 7, 8093 Zurich, Switzerland
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  • Raphael Ripamonti
    Affiliations
    Institute of Molecular Health Sciences, Department of Biology, Swiss Federal Institute of Technology (ETH) Zurich, Otto-Stern-Weg 7, 8093 Zurich, Switzerland
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  • Hiroshi Kawabe
    Affiliations
    Department of Molecular Neurobiology, Max-Planck-Institute of Experimental Medicine, Hermann-Rein-Strasse 3, 37075 Göttingen, Germany

    Department of Pharmacology, Gunma University Graduate School of Medicine, 3-39-22 Showa-machi, Maebashi, Gunma 317-8511, Japan
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  • Author Footnotes
    + Joint senior authors
    Maya Ben-Yehuda Greenwald
    Footnotes
    + Joint senior authors
    Affiliations
    Institute of Molecular Health Sciences, Department of Biology, Swiss Federal Institute of Technology (ETH) Zurich, Otto-Stern-Weg 7, 8093 Zurich, Switzerland
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  • Author Footnotes
    + Joint senior authors
    Sabine Werner
    Correspondence
    Correspondence: Prof. Dr. Sabine Werner:
    Footnotes
    + Joint senior authors
    Affiliations
    Institute of Molecular Health Sciences, Department of Biology, Swiss Federal Institute of Technology (ETH) Zurich, Otto-Stern-Weg 7, 8093 Zurich, Switzerland
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  • Author Footnotes
    + Joint senior authors
Published:October 27, 2021DOI:https://doi.org/10.1016/j.jid.2021.09.033

      ABSTRACT

      The ubiquitin ligase Nedd4-1 plays key roles in organ development, tissue homeostasis and cancer, but its functions in the skin are largely unknown. Here we show perturbations in keratinocyte proliferation and terminal differentiation, epidermal barrier function, and hair follicle cycling as well as increased UV-induced apoptosis in mice lacking Nedd4-1 in keratinocytes. In particular, re-epithelialization of full-thickness excisional wounds was delayed in the mutant mice. This was caused by severely impaired migration and proliferation of Nedd4-1-deficient keratinocytes. Therefore, a few keratinocytes, which had escaped recombination and expressed Nedd4-1, obtained a growth advantage and contributed to re-epithelialization. Mechanistically, Nedd4-1-deficient keratinocytes failed to efficiently activate the Erk1/2 mitogen-activated kinases and the YAP transcriptional co-activator. These results identify Nedd4-1 as an essential player in wound repair through its effect on mitogenic and motogenic signaling pathways in keratinocytes.

      Abbreviations used:

      D (Dermis), EGF (Epidermal growth factor), EGFR (Epidermal growth factor receptor), Es (Eschar), GT (Granulation tissue), HE (Hyperproliferative epidermis), HF (Hair follicle), LATS1 (Large tumor suppressor), NEDD4 (Neuronal precursor cell-expressed developmentally down-regulated 4), WE (Wound epidermis), YAP (Yes-associated protein)
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