title: 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.
abstract: 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.
authors.affiliation: Department of Dermatology, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China. zhgdoc@hotmail.com.
authors.forename: Hengguang
authors.initials: H
authors.lastname: Zhao
authors.affiliation: Kathryn W. Davis Center for Regenerative Biology and Medicine, Mount Desert Island Biological Laboratory, 159 Old Bar Harbor Road, Salisbury Cove, ME 04672, USA. srieger@mdibl.org.
authors.forename: Sandra
authors.initials: S
authors.lastname: Rieger
authors.affiliation: Department of Molecular Life Science, Tokai University School of Medicine, Isehara, Kanagawa 259-1193, Japan. abeko@is.icc.u-tokai.ac.jp.
authors.forename: Koichiro
authors.initials: K
authors.lastname: Abe
authors.affiliation: Institute of Metabolism and Systems Research, College of Medical and Dental Sciences, The University of Birmingham, Birmingham B15 2TH, UK. m.hewison@bham.ac.uk.
authors.forename: Martin
authors.initials: M
authors.lastname: Hewison
authors.affiliation: Kathryn W. Davis Center for Regenerative Biology and Medicine, Mount Desert Island Biological Laboratory, 159 Old Bar Harbor Road, Salisbury Cove, ME 04672, USA. thomas.lisse@jax.org.|The Jackson Laboratory, Bar Harbor, ME 04609, USA. thomas.lisse@jax.org.
authors.forename: Thomas S
authors.initials: TS
authors.lastname: Lisse
mesh_terms: D000818:Animals; D004817:Epidermis / Q000378:metabolism; D018859:Hair Follicle / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D011485:Protein Binding; D062326:Re-Epithelialization / Q000235:genetics / Q000502:physiology*; D018167:Receptors, Calcitriol / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology; D013312:Stress, Physiological; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014945:Wound Healing / Q000502:physiology
chemical_list: C469992:Ddit4 protein, mouse; D018167:Receptors, Calcitriol; D014157:Transcription Factors
keywords: DDIT4; VDR; hair follicle; mTOR; stem cells; stress; wound repair