Development and progression of alopecia in the vitamin D receptor null mouse

Abstract

Humans with selected mutations in the vitamin D receptor (VDR) and mouse models lacking VDR develop alopecia. Mice null for the Vdr gene are born with a normal coat of hair, but fail to initiate normal hair follicle cycling. In this study, we examined the morphology of the hair follicle of the Vdr null mouse during days 13-22 when the hair follicle normally initiates and completes the first catagen. We then explored the possibility that the abnormality in hair follicle cycling was associated with abnormal expression of hairless (Hr), a putative transcriptional regulator known to regulate hair follicle cycling and recently shown to regulate VDR transcriptional activity. Our results demonstrate the progressive deterioration of the hair follicle through catagen. Comparable to VDR, Hr was found in the basal cells of the epidermis and ORS of the hair follicle. However, Hr was also found in the IRS and matrix of the follicle, regions with little or no VDR. Hr levels increased during catagen, reaching a peak by day 19. Levels of Hr were greater in the Vdr null mice compared to wildtype controls, results confirmed by quantitative RT-PCR. We conclude that lack of VDR causes disruption of hair follicle structure during the first catagen resulting in failure of subsequent hair follicle cycling. These changes are associated with increased expression of Hr, suggesting a role for VDR in regulating Hr expression. Both Hr and VDR are required for normal hair follicle cycling.

Sequential regulation of keratinocyte differentiation by 1,25(OH)2D3, VDR, and its coregulators

“…Mutations in hairless (HR) [20] result in a phenotype similar to that seen in the VDR null mouse in that the developmental hair follicle cycle is normal, but the postnatal hair follicle cycle is blocked. We have found VDR and HR in the nuclei of keratinocytes in the stratum basale and outer root sheath [21]. HR has characteristics of a transcription factor in which it resides in the nucleus; its structure contains a nuclear localization signal, a putative zinc finger, and three LXXLL motifs [22] like that found in coactivators that interact with nuclear hormone receptors such as VDR as well as XX motifs ( = hydrophobic amino acid) similar to regions in corepressors like SMRT and NCoR responsible for the binding of these corepressors to nuclear hormone receptors.…”

Novel mechanisms for the vitamin D receptor (VDR) in the skin and in skin cancer

“…Normally during catagen the dermal papilla stays attached to the receding proximal (cycling) part of the hair follicle to end up adjacent to the bulge as the follicle enters telogen. In the skin of mice in which the keratinocytes lack the VDR the dermal papilla separates from the hair follicle during catagen, and anagen is not reinitiated (2). Both the wnt/β-catenin and sonic hedgehog pathway are important for hair follicle cycling, and as we will discuss in the section on skin cancer, part of the mechanism by which VDR controls hair follicle cycling may involve these pathways (21).…”

“…Mutations or deletion of VDR and CYP27B1 results in hyperproliferation of the cells within the basal layer as well as defects in permeability barrier formation and the innate immune response. Loss of VDR also disrupts hair follicle cycling leading to alopecia, but this role of VDR appears to be independent of 1,25(OH) 2 D in that mutations or deletion of CYP27B1 does not disrupt hair follicle cycling (2,3). …”

Premature aging in vitamin D receptor mutant mice

“…Solving the problem of survival of the VDR KO mice by feeding a special rescue diet opened up possibilities to study the role of vitamin D 3 deficiency in aging [41]. Our preliminary studies suggested that most of the phenotypical features shown in the VDR KO mice might be related to premature aging [3,18,[42][43][44] In the present study, we analyzed aging in VDR KO mice by measuring survival, weight gain, skin and cerebellum morphology, swimming and expression of different aging-related genes.…”