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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.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.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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EB1089 stimulates differentiation of ectopic hair follicles formation in the D4 line of K14ΔNβ-cateninER transgenic mice.Epidermal whole mounts (A–D) or sections (E–X) of wild type (WT) or transgenic (β-cat-D4) tail skin treated with 4OHT and/or EB1089. (A–D) Immunolabelling for keratin 17 (green) with Hoechst (blue) and phalloidin-TRITC (red) counterstaining. Arrows indicate ectopic hair follicles in the IFE (B, C) or SG (D). Inserts in (B, C) show higher magnification views of ectopic follicles. (E–X) Immunolabelling with the antibodies shown (green) in combination with Hoechst (blue; E–X), phalloidin-TRICT (red; E, F) or anti-keratin 14 (red; g-v). (C) Dashed square indicates an epidermal unit as previously described [5]. (F) Arrow indicates keratin 15 expression in ORS of ectopic HF. Insert shows base of an ectopic follicle. (K) Cells expressing K31 are indicated by an arrow and shown at higher magnification in insert. Asterisks indicate base of ectopic HFs encircling dermal papilla (F, S, N, X). Scale bars: 100 µm (A–D), 50 µm (E–X).
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pone-0001483-g003: EB1089 stimulates differentiation of ectopic hair follicles formation in the D4 line of K14ΔNβ-cateninER transgenic mice.Epidermal whole mounts (A–D) or sections (E–X) of wild type (WT) or transgenic (β-cat-D4) tail skin treated with 4OHT and/or EB1089. (A–D) Immunolabelling for keratin 17 (green) with Hoechst (blue) and phalloidin-TRITC (red) counterstaining. Arrows indicate ectopic hair follicles in the IFE (B, C) or SG (D). Inserts in (B, C) show higher magnification views of ectopic follicles. (E–X) Immunolabelling with the antibodies shown (green) in combination with Hoechst (blue; E–X), phalloidin-TRICT (red; E, F) or anti-keratin 14 (red; g-v). (C) Dashed square indicates an epidermal unit as previously described [5]. (F) Arrow indicates keratin 15 expression in ORS of ectopic HF. Insert shows base of an ectopic follicle. (K) Cells expressing K31 are indicated by an arrow and shown at higher magnification in insert. Asterisks indicate base of ectopic HFs encircling dermal papilla (F, S, N, X). Scale bars: 100 µm (A–D), 50 µm (E–X).

Mentions: To examine whether β-catenin and the VDR also cooperated to promote hair follicle differentiation in vivo in adult epidermis, we tested the effect of EB1089 on 4OHT treated K14ΔNβ-cateninER transgenic mice from two founder lines, D2 and D4. Activation of β-catenin stimulates proliferation and anagen entry in both high (D4) and low (D2) transgenic copy number mouse lines [5], [6]. Proliferation is stimulated to a greater extent in the D4 line, whereas ectopic HF morphogenesis is more advanced in the D2 line. The doses of EB1089 and 4OHT used did not induce epidermal changes in wild type mice (Figure 3A).


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)

EB1089 stimulates differentiation of ectopic hair follicles formation in the D4 line of K14ΔNβ-cateninER transgenic mice.Epidermal whole mounts (A–D) or sections (E–X) of wild type (WT) or transgenic (β-cat-D4) tail skin treated with 4OHT and/or EB1089. (A–D) Immunolabelling for keratin 17 (green) with Hoechst (blue) and phalloidin-TRITC (red) counterstaining. Arrows indicate ectopic hair follicles in the IFE (B, C) or SG (D). Inserts in (B, C) show higher magnification views of ectopic follicles. (E–X) Immunolabelling with the antibodies shown (green) in combination with Hoechst (blue; E–X), phalloidin-TRICT (red; E, F) or anti-keratin 14 (red; g-v). (C) Dashed square indicates an epidermal unit as previously described [5]. (F) Arrow indicates keratin 15 expression in ORS of ectopic HF. Insert shows base of an ectopic follicle. (K) Cells expressing K31 are indicated by an arrow and shown at higher magnification in insert. Asterisks indicate base of ectopic HFs encircling dermal papilla (F, S, N, X). Scale bars: 100 µm (A–D), 50 µm (E–X).
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Related In: Results  -  Collection

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

pone-0001483-g003: EB1089 stimulates differentiation of ectopic hair follicles formation in the D4 line of K14ΔNβ-cateninER transgenic mice.Epidermal whole mounts (A–D) or sections (E–X) of wild type (WT) or transgenic (β-cat-D4) tail skin treated with 4OHT and/or EB1089. (A–D) Immunolabelling for keratin 17 (green) with Hoechst (blue) and phalloidin-TRITC (red) counterstaining. Arrows indicate ectopic hair follicles in the IFE (B, C) or SG (D). Inserts in (B, C) show higher magnification views of ectopic follicles. (E–X) Immunolabelling with the antibodies shown (green) in combination with Hoechst (blue; E–X), phalloidin-TRICT (red; E, F) or anti-keratin 14 (red; g-v). (C) Dashed square indicates an epidermal unit as previously described [5]. (F) Arrow indicates keratin 15 expression in ORS of ectopic HF. Insert shows base of an ectopic follicle. (K) Cells expressing K31 are indicated by an arrow and shown at higher magnification in insert. Asterisks indicate base of ectopic HFs encircling dermal papilla (F, S, N, X). Scale bars: 100 µm (A–D), 50 µm (E–X).
Mentions: To examine whether β-catenin and the VDR also cooperated to promote hair follicle differentiation in vivo in adult epidermis, we tested the effect of EB1089 on 4OHT treated K14ΔNβ-cateninER transgenic mice from two founder lines, D2 and D4. Activation of β-catenin stimulates proliferation and anagen entry in both high (D4) and low (D2) transgenic copy number mouse lines [5], [6]. Proliferation is stimulated to a greater extent in the D4 line, whereas ectopic HF morphogenesis is more advanced in the D2 line. The doses of EB1089 and 4OHT used did not induce epidermal changes in wild type mice (Figure 3A).

Bottom Line: 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.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