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Int. J. Mol. Sci. 2016, 17(12), 1984; doi:10.3390/ijms17121984

DNA Damage-Inducible Transcript 4 Is an Innate Surveillant of Hair Follicular Stress in Vitamin D Receptor Knockout Mice and a Regulator of Wound Re-Epithelialization

Department of Dermatology, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China
Kathryn W. Davis Center for Regenerative Biology and Medicine, Mount Desert Island Biological Laboratory, 159 Old Bar Harbor Road, Salisbury Cove, ME 04672, USA
Department of Molecular Life Science, Tokai University School of Medicine, Isehara, Kanagawa 259-1193, Japan
Institute of Metabolism and Systems Research, College of Medical and Dental Sciences, The University of Birmingham, Birmingham B15 2TH, UK
The Jackson Laboratory, Bar Harbor, ME 04609, USA
Authors to whom correspondence should be addressed.
Academic Editor: Allison Cowin
Received: 19 October 2016 / Revised: 7 November 2016 / Accepted: 22 November 2016 / Published: 26 November 2016
(This article belongs to the Special Issue Wound Repair and Regeneration)
View Full-Text   |   Download PDF [6076 KB, uploaded 26 November 2016]   |  


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. View Full-Text
Keywords: wound repair; VDR; mTOR; DDIT4; stress; hair follicle; stem cells wound repair; VDR; mTOR; DDIT4; stress; hair follicle; stem cells

This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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MDPI and ACS Style

Zhao, H.; Rieger, S.; Abe, K.; Hewison, M.; Lisse, T.S. DNA Damage-Inducible Transcript 4 Is an Innate Surveillant of Hair Follicular Stress in Vitamin D Receptor Knockout Mice and a Regulator of Wound Re-Epithelialization. Int. J. Mol. Sci. 2016, 17, 1984.

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