DNA damage inducible transcript 4 is an innate surveillant of hair follicular stress in vitamin D receptor knockout mice and regulator of wound re-epithelialization

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Colleges, School and Institutes

External organisations

  • Department of Dermatology, The First Affliated Hospital of Chongqing Medical University, Chongqing 400016, China
  • Kathryn W Davies Center for Regenerative Biology and Medicine, Mount Desert Island Biological Laboratory, 159 Old Bar Harbor Road, Sailsbury Cove, ME 04672, USA
  • Department of Molecular Life Science, Tokai University School of Medicine, Isehara, Kanagawa 259-1193, Japan


Mice and human patients with impaired vitamin D receptor (VDR) signaling have normal developmental hair growth but display aberrant post-morphogenic hair cycle progression associated with alopecia. In addition, VDR–/– mice exhibit impaired cutaneous wound healing. We undertook experiments to determine whether the stress-inducible regulator of energy homeostasis, DNA damage-inducible transcript 4 (Ddit4), is involved in these processes. By analyzing hair cycle activation in vivo, we show that VDR−/− mice at day 14 exhibit increased Ddit4 expression within follicular stress compartments. At day 29, degenerating VDR−/− follicular keratinocytes, but not bulge stem cells, continue to exhibit an increase in Ddit4 expression. At day 47, when normal follicles and epidermis are quiescent and enriched for Ddit4, VDR−/− skin lacks Ddit4 expression. In a skin wound healing assay, the re-epithelialized epidermis in wildtype (WT) but not VDR−/− animals harbor a population of Ddit4- and Krt10-positive cells. Our study suggests that VDR regulates Ddit4 expression during epidermal homeostasis and the wound healing process, while elevated Ddit4 represents an early growth-arresting stress response within VDR−/− follicles.


Original languageEnglish
JournalInternational Journal of Molecular Sciences
Issue number12
Publication statusPublished - 26 Nov 2016