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The vitamin D receptor is a Wnt effector that controls hair follicle differentiation and specifies tumor type in adult epidermis.

Pálmer HG, Anjos-Afonso F, Carmeliet G, Takeda H, Watt FM - PLoS ONE (2008)

Bottom Line: We have investigated how Wnt and vitamin D receptor signals regulate epidermal differentiation.The VDR is required for beta-catenin induced hair follicle formation in adult epidermis, and the vitamin D analog EB1089 synergizes with beta-catenin to stimulate hair differentiation.We conclude that VDR is a TCF/Lef-independent transcriptional effector of the Wnt pathway and that vitamin D analogues have therapeutic potential in tumors with inappropriate activation of Wnt signalling.

View Article: PubMed Central - PubMed

Affiliation: Cancer Research UK Cambridge Research Institute, Li Ka Shing Centre, Cambridge, United Kingdom.

ABSTRACT
We have investigated how Wnt and vitamin D receptor signals regulate epidermal differentiation. Many epidermal genes induced by beta-catenin, including the stem cell marker keratin 15, contain vitamin D response elements (VDREs) and several are induced independently of TCF/Lef. The VDR is required for beta-catenin induced hair follicle formation in adult epidermis, and the vitamin D analog EB1089 synergizes with beta-catenin to stimulate hair differentiation. Human trichofolliculomas (hair follicle tumours) are characterized by high nuclear beta-catenin and VDR, whereas infiltrative basal cell carcinomas (BCCs) have high beta-catenin and low VDR levels. In mice, EB1089 prevents beta-catenin induced trichofolliculomas, while in the absence of VDR beta-catenin induces tumours resembling BCCs. We conclude that VDR is a TCF/Lef-independent transcriptional effector of the Wnt pathway and that vitamin D analogues have therapeutic potential in tumors with inappropriate activation of Wnt signalling.

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Related in: MedlinePlus

VDR is necessary for differentiation of β-catenin induced hair follicles.Mice were wild-type or D2 K14ΔNβ-cateninER transgenics, heterozygous (+/−) or homozygous (−/−)  for the VDR and had been treated with 4OHT for 21 days. (A–D) Macroscopic views of tail skin showing extent of hair growth. (E–L) Tail epidermal whole mounts immunolabelled with the antibodies indicated (green) and counterstained with Hoechst (blue) and phalloidin-TRICT (red). Arrows and dotted lines indicate ectopic HFs arising from SGs and arrowheads indicate residual HFs. Asterisks show nonspecific SG staining. (M-B') Immunostaining of tail skin sections with the antibodies indicated (green) and anti-keratin 14 (red) with Hoechst counterstain (blue). Scale bars: 100 µm.
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pone-0001483-g004: VDR is necessary for differentiation of β-catenin induced hair follicles.Mice were wild-type or D2 K14ΔNβ-cateninER transgenics, heterozygous (+/−) or homozygous (−/−) for the VDR and had been treated with 4OHT for 21 days. (A–D) Macroscopic views of tail skin showing extent of hair growth. (E–L) Tail epidermal whole mounts immunolabelled with the antibodies indicated (green) and counterstained with Hoechst (blue) and phalloidin-TRICT (red). Arrows and dotted lines indicate ectopic HFs arising from SGs and arrowheads indicate residual HFs. Asterisks show nonspecific SG staining. (M-B') Immunostaining of tail skin sections with the antibodies indicated (green) and anti-keratin 14 (red) with Hoechst counterstain (blue). Scale bars: 100 µm.

Mentions: VDR heterozygous mice were indistinguishable from wild type (Figure 4A). Although in some VDR−/− mice alopecia develops as early as 3 weeks after birth [20], alopecia was not yet evident in our 8 week old VDR −/− mice (Figure 4C and data not shown). Nevertheless, the HFs were thin and elongated. Although K17 was expressed (Figure 4G) K15 was undetectable (Figure 4K), providing confirmation of our finding that both β-catenin and VDR must be activated in order for the K15 gene to be transcribed (Figure 2). The absence of VDR was confirmed by antibody staining (Figure S4A, B).


The vitamin D receptor is a Wnt effector that controls hair follicle differentiation and specifies tumor type in adult epidermis.

Pálmer HG, Anjos-Afonso F, Carmeliet G, Takeda H, Watt FM - PLoS ONE (2008)

VDR is necessary for differentiation of β-catenin induced hair follicles.Mice were wild-type or D2 K14ΔNβ-cateninER transgenics, heterozygous (+/−) or homozygous (−/−)  for the VDR and had been treated with 4OHT for 21 days. (A–D) Macroscopic views of tail skin showing extent of hair growth. (E–L) Tail epidermal whole mounts immunolabelled with the antibodies indicated (green) and counterstained with Hoechst (blue) and phalloidin-TRICT (red). Arrows and dotted lines indicate ectopic HFs arising from SGs and arrowheads indicate residual HFs. Asterisks show nonspecific SG staining. (M-B') Immunostaining of tail skin sections with the antibodies indicated (green) and anti-keratin 14 (red) with Hoechst counterstain (blue). Scale bars: 100 µm.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2198947&req=5

pone-0001483-g004: VDR is necessary for differentiation of β-catenin induced hair follicles.Mice were wild-type or D2 K14ΔNβ-cateninER transgenics, heterozygous (+/−) or homozygous (−/−) for the VDR and had been treated with 4OHT for 21 days. (A–D) Macroscopic views of tail skin showing extent of hair growth. (E–L) Tail epidermal whole mounts immunolabelled with the antibodies indicated (green) and counterstained with Hoechst (blue) and phalloidin-TRICT (red). Arrows and dotted lines indicate ectopic HFs arising from SGs and arrowheads indicate residual HFs. Asterisks show nonspecific SG staining. (M-B') Immunostaining of tail skin sections with the antibodies indicated (green) and anti-keratin 14 (red) with Hoechst counterstain (blue). Scale bars: 100 µm.
Mentions: VDR heterozygous mice were indistinguishable from wild type (Figure 4A). Although in some VDR−/− mice alopecia develops as early as 3 weeks after birth [20], alopecia was not yet evident in our 8 week old VDR −/− mice (Figure 4C and data not shown). Nevertheless, the HFs were thin and elongated. Although K17 was expressed (Figure 4G) K15 was undetectable (Figure 4K), providing confirmation of our finding that both β-catenin and VDR must be activated in order for the K15 gene to be transcribed (Figure 2). The absence of VDR was confirmed by antibody staining (Figure S4A, B).

Bottom Line: We have investigated how Wnt and vitamin D receptor signals regulate epidermal differentiation.The VDR is required for beta-catenin induced hair follicle formation in adult epidermis, and the vitamin D analog EB1089 synergizes with beta-catenin to stimulate hair differentiation.We conclude that VDR is a TCF/Lef-independent transcriptional effector of the Wnt pathway and that vitamin D analogues have therapeutic potential in tumors with inappropriate activation of Wnt signalling.

View Article: PubMed Central - PubMed

Affiliation: Cancer Research UK Cambridge Research Institute, Li Ka Shing Centre, Cambridge, United Kingdom.

ABSTRACT
We have investigated how Wnt and vitamin D receptor signals regulate epidermal differentiation. Many epidermal genes induced by beta-catenin, including the stem cell marker keratin 15, contain vitamin D response elements (VDREs) and several are induced independently of TCF/Lef. The VDR is required for beta-catenin induced hair follicle formation in adult epidermis, and the vitamin D analog EB1089 synergizes with beta-catenin to stimulate hair differentiation. Human trichofolliculomas (hair follicle tumours) are characterized by high nuclear beta-catenin and VDR, whereas infiltrative basal cell carcinomas (BCCs) have high beta-catenin and low VDR levels. In mice, EB1089 prevents beta-catenin induced trichofolliculomas, while in the absence of VDR beta-catenin induces tumours resembling BCCs. We conclude that VDR is a TCF/Lef-independent transcriptional effector of the Wnt pathway and that vitamin D analogues have therapeutic potential in tumors with inappropriate activation of Wnt signalling.

Show MeSH
Related in: MedlinePlus