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Ligand-Independent Actions of the Vitamin D Receptor Maintain Hair Follicle Homeostasis

Endocrine Unit (K.S., M.C., M.B.D.), Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114; Kennedy Krieger Institute and Department of Neuroscience (J.M.S., C.C.T.), Johns Hopkins University School of Medicine, Baltimore 21205, Maryland; and Department of Pharmacology (D.R.D., P.N.M.), Case Western Reserve University, Cleveland, Ohio 44106

Address all correspondence and requests for reprints to: Marie B. Demay, Wellman 501, Massachusetts General Hospital, 50 Blossom Street, Boston, Massachusetts 02114. E-mail:demay{at}helix.mgh.harvard.edu.

Alopecia is a feature of vitamin D receptor (VDR) mutations in humans and in VDR null mice. This alopecia results from an inability to initiate the anagen phase of the hair cycle after follicle morphogenesis is complete. Thus, once the initial hair is shed it does not regrow. VDR expression in the epidermal component of the hair follicle, the keratinocyte, is critical for maintenance of the hair cycle. To determine which functional domains of the VDR are required for hair cycling, mutant VDR transgenes were targeted to the keratinocytes of VDR null mice. Keratinocyte-specific expression of a VDR transgene with a mutation in the hormone-binding domain that abolishes ligand binding restores normal hair cycling in VDR null mice, whereas a VDR transgene with a mutation in the activation function 2 domain that impairs nuclear receptor coactivator recruitment results in a partial rescue. Mutations in the nuclear receptor corepressor Hairless are also associated with alopecia in humans and mice. Hairless binds the VDR, resulting in transcriptional repression. Neither VDR mutation affects Hairless interactions or its ability to repress transcription. These studies demonstrate that the effects of the VDR on the hair follicle are ligand independent and point to novel molecular and cellular actions of this nuclear receptor.

NURSA Molecule Pages Link:

Nuclear Receptors:   VDR

Coregulators:   RIP140  |  TRIP1  |  SRC-1

Ligands:   Calcitriol

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