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Regulation of hair follicle development by the TNF signal ectodysplasin and its receptor Edar

¹ Institute of Biotechnology, Viikki Biocenter, 00014 University of Helsinki, Finland
² Department of Dermatology, University of Helsinki, Finland
³ Gene Center and Institute of Biochemistry, University of Munich, Feodor Lynen Strasse 25, 81377 Munich, Germany

View larger version (84K): [in a new window]   Fig. 1. Expression of Eda (Ta, encoding the TNF ectodysplasin) and Edar (dl, encoding the TNF receptor Edar) during hair follicle development in the back skin. (A,B) Eda and Edar transcripts are co-expressed in the E12 embryonic ectoderm. (C-F) At E14-15, Eda expression continues in the ectoderm except in the newly formed placodes. The placodes express Edar intensely, whereas it is downregulated in the rest of the ectoderm. (G-H) Eda and Edar transcripts are intensely expressed in the bulb of newborn stage 3-6 hair follicles. Eda expression continues in the epidermis. Scale bar: 100 µm.

View larger version (52K): [in a new window]   Fig. 2. Stimulation of Edar expression (dl) in hair placodes by activin A but not by other signals. (A,B) Edar expression is stimulated by an activin A-releasing bead in placodes throughout the whole skin explant. (C) Activin A does not induce Edar expression in isolated skin epithelium. (D-I) None of the other tested signal proteins [BMP4, EGF, FGF10, SHH and WNT6 (introduced by cell aggregates)] or BSA control beads stimulated Edar expression. (J-L) Positive controls: (J) Msx2 expression induced by BMP4. (K) Ptch (Ptc) induced by SHH. (L) Lef1 induced by WNT6-expressing cells. Scale bar: 200 µm.

View larger version (94K): [in a new window]   Fig. 3. Stimulation of Edar (dl) expression by activin A in dental epithelium. (A,B) Activin A bead has stimulated Edar expression in the epithelial signaling center, the enamel knot in an E12 whole tooth germ. (C) Edar expression is not induced by activin A in isolated tooth epithelium. (D) BSA control beads did not stimulate Edar expression. Scale bar: 200 µm.

View larger version (76K): [in a new window]   Fig. 4. Induction of Eda (Ta) expression by WNT6 in skin epithelium. (A,B) WNT6-expressing cells stimulate Eda expression in whole skin explants (A) as well as in isolated epithelium (B). (C) 3T3 control cells failed to induce Eda. (D-H) None of the other signals tested (activin A, BMP4, EGF, FGF10 and SHH) had stimulatory effects on Eda expression. Scale bar: 200 µm.

View larger version (62K): [in a new window]   Fig. 5. Expression of Eda (Ta) and Edar (dl) in wild-type and Lef1–/– embryos. (A,C) Eda is expressed in the skin of E11 and E15 wild-type littermates of Lef1–/– embryos. (B,D) In the ectoderm of a Lef1–/– embryo, expression of Eda was almost completely absent. (E,G) Eda transcripts are seen in the epithelium as well as in the hair follicles in E17 and P0 wild-type littermates. (F) Eda transcripts are downregulated in Lef1–/– skin. (G) In P0, Lef1–/– skin, faint Eda expression is seen in the hair follicles. (I,J) Edar is expressed throughout the epithelium in E13 wild-type littermates and Lef1–/– embryos. (K,L) Edar transcripts are upregulated in the hair follicles in E17 wild-type littermates and Lef1–/– embryos. Scale bar: 100 µm.

View larger version (54K): [in a new window]   Fig. 6. Comparison of skin and hair follicle development between wild-type and Ta mutant embryos. (A,B) At E11, the ectoderm appears slightly thinner in Ta skin. (C,D) At E15, the first wave hair follicles (tylotrich or guard) are seen in wild-type skin whereas the Ta skin ectoderm is uniformly thin and devoid of hair placodes. (E,F) At E17, tylotrich hair follicles have developed into stage 3-4 in wild-type skin. Placodes of awl follicles (stage 1-2) have appeared in Ta skin (arrow) and the epidermis has increased in thickness. (G,H) At P0 (newborn), tylotrich (skeleton arrow) and awl follicles (arrow) are present in wild-type skin, whereas in Ta mice only awl follicles are seen. (I-N) Differentiation of the keratinocytes is not affected in Ta skin. (I,J) Keratin 14 is expressed in basal epithelial cells. (K,L) Keratin 10 is expressed in suprabasal cells. (M,N) Filaggrin (FIL) is expressed in differentiated keratinocytes. Broken lines indicate the interface between epithelium and mesenchyme. Scale bar: 100 µm.

View larger version (94K): [in a new window]   Fig. 7. Comparison of ectodermal gene expression patterns in wild-type and Ta mutant skin. (A,E,I) In E 15 ectoderm, Edar (dl) is expressed in the placodes of the first wave tylotrich hairs, and Lef1 (also expressed in the underlying mesenchyme) and Shh show similar expression in placodes. (C,G,K) At E17, the same genes are largely co-expressed in the developing tylotrich hair follicles (skeleton arrows) and in placodes of awl follicles (arrows). (B,F,J) In Ta mutant skin, no placodes have been initiated at E15 and expression of Edar, and Lef1 is seen throughout the ectoderm. Lef1 is also expressed in mesenchyme. (N) Shh transcripts are absent in E15 Ta mutant skin. (D,H,L) In E17 Ta skin, placodes of awl follicles have been initiated, and Edar and Shh are expressed in the placode ectoderm. (L) Lef1 expression is seen throughout the basal epithelium, in the placodes and also in underlying mesenchyme. Scale bar: 100 µm.

View larger version (79K): [in a new window]   Fig. 8. Comparison of gene expression in the skin mesenchyme of wild-type and Ta mutant embryos. (A,E,I) Activin ßA, Bmp4 and Ptch are intensely expressed in the mesenchyme under the ectodermal placodes in E15 wild-type embryos. Ptch (Ptc) expression is seen in whole mount in situ hybridization. (C,G,K) In E17 wild-type embryos, activin ßA, Bmp4 and Ptch are expressed in the tylotrich hair follicles and awl placodes. (B,F,J) In E15 Ta mutants, no placodes have formed and no upregulation of gene expression is apparent. Activin ßA is expressed weakly throughout the mesenchyme underlying the ectoderm. (D,H,L) At E17, activin ßA, Bmp4 and Ptch are intensely expressed in the Ta mesenchyme that underlies the placodes of awl hairs. Scale bar: 100 µm.

View larger version (93K): [in a new window]   Fig. 9. Expression of Wnt6, Wnt10a and ß-catenin in wild-type and Ta mutant embryos. (A,B) Wnt6 is expressed in the epithelium of both wild-type and Ta mutant E17 skin. (C-F) Wnt10a transcripts are expressed in the basal epithelial cell layer in wild-type and Ta mutant skin as well as in hair follicles. (G,H) ß-catenin is expressed in the epithelium and underlying mesenchyme in E15 wild-type and Ta mutant skin. (I-L) During later stages, ß-catenin transcripts become strongly upregulated in the hair follicles both in wild type and Ta mutant skin, and expression continues in the basal epithelium as well. Scale bar: 100 µm.

View larger version (35K): [in a new window]   Fig. 10. The regulation of hair follicle formation by the TNF signal ectodysplasin [encoded by Eda (Ta) gene] and its receptor Edar [encoded by Edar (dl) gene], and integration with other signaling pathways. Ectodysplasin is expressed in the interfollicular ectoderm and induced by WNT signals, which are transduced by LEF1. Edar is expressed in the placodes and stimulated by activin signals from the underlying mesenchyme. Ectodysplasin is shed (secreted) and binds as a trimer to the trimerized Edar receptor. This TNF signaling is transduced by the NF-B transcription factor.