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Noggin is a mesenchymally derived stimulator of hair-follicle induction

Nature Cell Biology volume 1, pages 158–164 (1999)Cite this article

Abstract

The induction of developmental structures derived from the ectoderm, such as the neural tube or tooth, occurs through neutralization of the inhibitory activity of members of the bone-morphogenetic protein (BMP) family by BMP antagonists. Here we show that, during hair-follicle development, the neural inducer and BMP-neutralizing protein Noggin is expressed in the follicular mesenchyme, that noggin-knockout mice show significant retardation of hair-follicle induction, and that Noggin neutralizes the inhibitory action of BMP-4 and stimulates hair-follicle induction in embryonic skin organ culture. As a crucial mesenchymal signal that stimulates hair-follicle induction, Noggin operates through antagonistic interactions with BMP-4, which result in upregulation of the transcription factor Lef-1 and the cell-adhesion molecule NCAM, as well as through BMP4-independent downregulation of the 75 kD neurotrophin receptor in the developing hair follicle.

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Figure 1: Summary of noggin expression during hair-follicle morphogenesis.
Figure 2: Expression of noggin in the developing hair follicle.
Figure 3: Retardation of hair-follicle induction and morphogenesis in noggin -knockout mice.
Figure 4: Noggin antagonizes BMP-4 and stimulates hair-follicle induction in embryonic skin organ culture.
Figure 5: Expression of transcription factors, adhesion molecules, cytokeratins and morphogens and their receptors in the skin of wild-type and noggin mutant embryos.
Figure 6: Expression of Lef-1, NCAM, p75NTR, CK10 and CK14 in skin explants cultured in the presence of Noggin- and BMP4-soaked beads.
Figure 7: Potential molecular targets for Noggin during hair-follicle induction.

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References

  1. Lamb, T. M. et al. Neural induction by the secreted polypeptide noggin. Science 262, 713–718 ( 1993).

    Article  CAS  Google Scholar 

  2. Neubüser, A., Peters, H., Balling, R. & Martin, G. R. Antagonistic interactions between FGF and BMP signaling pathways: a mechanism for positioning the sites of tooth formation. Cell 90, 247 –255 (1997).

    Article  Google Scholar 

  3. Jung, H. S. et al. Local inhibitory action of BMPs and their relationships with activators in feather formation: implications for periodic patterning. Dev. Biol. 196, 11–23 ( 1998).

    Article  CAS  Google Scholar 

  4. Tanabe, Y. & Jessel, T. M. Diversity and pattern in the developing spinal cord. Science 274, 1115 – 1123 (1996).

    Article  CAS  Google Scholar 

  5. Harland, R. & Gerhart, J. Formation and function of Spemann"s organizer. Annu. Rev. Cell Dev. Biol. 13, 611–667 (1997).

    Article  CAS  Google Scholar 

  6. Harland, R. M. Neural induction in Xenopus. Curr. Opin. Genet. Dev. 4, 543–549 (1994).

    Article  CAS  Google Scholar 

  7. Zimmerman, L. B., De Jesus Escobar, J. M. & Harland, R. M. The Spemann organizer signal noggin binds and inactivates bone morphogenetic protein 4. Cell 86, 599–606 (1996).

    Article  CAS  Google Scholar 

  8. McMahon, J. A. et al. Noggin-mediated antagonism of BMP signaling is required for growth and patterning of the neural tube and somite. Genes Dev . 12, 1438–1452 ( 1998).

    Article  CAS  Google Scholar 

  9. Tucker, A. S., Matthews, K. L. & Sharpe, P. T. Transformation of tooth type induced by inhibition of BMP signaling. Science 282, 1136– 1138 (1998).

    Article  CAS  Google Scholar 

  10. Hardy, M. H. The secret life of the hair follicle. Trends Genet. 8, 55–61 (1992).

    Article  CAS  Google Scholar 

  11. Oro, A. E. & Scott, M. P. Splitting hairs: dissecting roles of signaling systems in epidermal development. Cell 96, 575–578 (1998).

    Article  Google Scholar 

  12. Philpott, M. P. & Paus, R. in Molecular Basis of Epithelial Appendage Morphogenesis (ed. Chuong, C. M.) 75– 103 (Landes Bioscience, Austin, 1998).

    Google Scholar 

  13. van Genderen, C. et al. Development of several organs that require inductive epithelial-mesenchymal interactions is impaired in LEF-1-deficient mice. Genes Dev. 15, 2691–2703 (1994).

    Article  Google Scholar 

  14. Zhou, P., Byrne, C., Jacobs, J. & Fuchs, E. Lymphoid enhancer factor 1 directs hair follicle patterning and epithelial cell fate. Genes Dev. 9, 700–713 ( 1995).

    Article  CAS  Google Scholar 

  15. Gat, U., DasGupta, R., Degenstein, L. & Fuchs, E. De novo hair follicle morphogenesis and hair tumors in mice expressing a truncated beta-catenin in skin. Cell 95, 605–614 (1998).

    Article  CAS  Google Scholar 

  16. St-Jacques, B. et al. Sonic hedgehog signalling is essential for hair development . Curr. Biol 24, 1058–1068 (1998).

    Article  Google Scholar 

  17. Chiang, C. et al. Essential role for Sonic hedgehog during hair follicle morphogenesis . Dev. Biol. 205, 1–9 (1999).

    Article  CAS  Google Scholar 

  18. Winnier, G., Blessing, M., Labosky, P. A. & Hogan, B. L. Bone morphogenetic protein-4 is required for mesoderm formation and patterning in the mouse. Genes Dev. 9, 2105– 2116 (1995).

    Article  CAS  Google Scholar 

  19. Mishina, Y., Suzuki, A., Ueno, N. & Behringer, R. R. Bmpr encodes a type I bone morphogenetic protein receptor that is essential for gastrulation during mouse embryogenesis. Genes Dev. 9, 3027–3037 (1995).

    Article  CAS  Google Scholar 

  20. Hogan, B. L. Bone morphogenetic proteins in development. Curr. Opin. Genet. Dev. 6, 432–438 ( 1996).

    Article  CAS  Google Scholar 

  21. Blessing, M., Nanney, L. B., King, L. E., Jones, C. M. & Hogan, B. L. Transgenic mice as a model to study the role of TGF-beta-related molecules in hair follicles. Genes Dev. 7, 204–215 ( 1993).

    Article  CAS  Google Scholar 

  22. Lyons, K. M., Pelton, R. W. & Hogan, B. L. Organogenesis and pattern formation in the mouse: RNA distribution patterns suggest a role for bone morphogenetic protein-2A (BMP-2A). Development 109, 833– 844 (1990).

    CAS  PubMed  Google Scholar 

  23. Bitgood, M. J. & McMahon, A. P. Hedgehog and Bmp genes are coexpressed at many diverse sites of cell-cell interaction in the mouse embryo. Dev. Biol. 172, 126 – 138 (1995).

    Article  CAS  Google Scholar 

  24. Jahoda, C. A., Horne, K. A. & Oliver, R. F. Induction of hair growth by implantation of cultured dermal papilla cells. Nature 311, 560– 562 (1984).

    Article  CAS  Google Scholar 

  25. Jahoda, A. B. & Reynolds, A. J. Dermal-epidermal interactions — adult follicle-derived cell populations and hair growth. Dermatol. Clin. 14, 573–583 (1996).

    Article  CAS  Google Scholar 

  26. Polakowska, R. R., Piacentini, M., Bartlett, R., Goldsmith, L. A. & Haake, A. R. Apoptosis in human skin development: morphogenesis, periderm, and stem cells. Dev. Dyn. 199, 176–188 (1994).

    Article  CAS  Google Scholar 

  27. Botchkarev, V. A. et al. A new role for neurotrophins: involvement of brain-derived neurotrophic factor and neurotrophin-4 in hair cycle control. FASEB J. 13, 395–410 ( 1999).

    Article  CAS  Google Scholar 

  28. Hardy, M. H. & Vielkind, U. Changing patterns of cell adhesion molecules during mouse pelage hair follicle development. 1. Follicle morphogenesis in wild-type mice. Acta Anat. 157, 169– 182 (1996).

    Article  CAS  Google Scholar 

  29. Kim, J. et al. Transcriptional regulation of BMP-4 in the Xenopus embryo: analysis of genomic BMP-4 and its promoter. Biochem. Biophys. Res. Commun. 250, 516–530 ( 1998).

    Article  CAS  Google Scholar 

  30. Kratochwill, K., Dull, M., Farinas, I., Galceran, J. & Grosscheldl, R. Lef1 expression is activated by BMP-4 and regulates inductive tissue interactions in tooth and hair development. Genes Dev. 10, 1382–1394 ( 1996).

    Article  Google Scholar 

  31. Müller-Röver, S., Peters, E. M. J., Botchkarev, V. A., Panteleyev, A. A. & Paus, R. Distinct patterns of N-CAM expression are associated with defined stages of murine hair follicle morphogenesis and regression. J. Histochem. Cytochem. 46, 1401–1409 (1998).

    Article  Google Scholar 

  32. Müller-Röver, S. & Paus, R. in Molecular Biology of Epithelial Appendage Morphogenesis (ed. Chuong, C. M.) 283 – 314 (Landes Bioscience, Austin, 1998).

    Google Scholar 

  33. Holbrook, K. A. & Minami, S. I. Hair follicle embryogenesis in the human. Characterization of events in vivo and in vitro. Ann. NY Acad. Sci. 642, 167 –196 (1991).

    Article  CAS  Google Scholar 

  34. Byrne, C., Tainsky, M. & Fuchs, E. Programming gene expression in developing epidermis . Development 120, 2369– 2383 (1994).

    CAS  PubMed  Google Scholar 

  35. Eckert, R. L., Crish, J. F. & Robinson, N. A. The epidermal keratinocyte as a model for the study of gene regulation and cell differentiation. Physiol. Rev. 77, 397–424 (1997).

    Article  CAS  Google Scholar 

  36. Schmidt, C., Christ, B., Patel, K. & Brand-Saberi, B. Experimental induction of BMP-4 expression leads to apoptosis in the paraxial and lateral plate mesoderm. Dev. Biol. 202, 253– 263 (1998).

    Article  CAS  Google Scholar 

  37. Buckland, R. A., Collinson, J. M., Graham, E., Davidson, D. R. & Hill, R. E. Antagonistic effects of FGF4 on BMP induction of apoptosis and chondrogenesis in the chick limb bud. Mech. Dev. 71, 143–150 ( 1998).

    Article  CAS  Google Scholar 

  38. Dassule, H. & McMahon, A. P. Analysis of epithelial-mesenchymal interactions in the initial morphogenesis of the mammalian tooth. Dev. Biol. 202, 215–227 (1998).

    Article  CAS  Google Scholar 

  39. Chan, E. F., Gat, U., McNiff, J. M., & Fuchs, E. A common human skin tumour is caused by activating mutations in β-catenin. Nature Genet. 21, 410–413 ( 1999).

    Article  CAS  Google Scholar 

  40. Jiang, T. X. & Chuong, C.-M. Mechanism of skin morphogenesis. I. Analyses with antibodies to adhesion molecules tenascin, N-CAM, and integrin . Dev. Biol. 150, 82–98 (1992).

    Article  CAS  Google Scholar 

  41. Brunet, L. J., McMahon, J. A., McMahon, A. P. & Harland, R. M. Noggin, cartilage morphogenesis, and joint formation in the mammalian skeleton . Science 280, 1455–1457 (1998).

    Article  CAS  Google Scholar 

  42. Paus, R., Hofmann, U., Eichmüller, S. & Czarnetzki, B. M. Distribution and changing density of gamma-delta T cells in murine skin during the induced hair cycle. Br. J. Dermatol. 130, 281–289 (1994).

    Article  CAS  Google Scholar 

  43. Cerletti, N. et al. Process for the production of biologically active protein (TGF-β). European Patent Application No. 0433 225 A1; filed June 19, 1991.

  44. Li, L., Paus, R., Slominski, A. & Hoffman, R. Skin histoculture assay for studying the hair cycle. In Vitro Cell. Dev. Biol. 28, 695–698 (1992).

    Article  Google Scholar 

  45. Botchkarev, V. A. et al. A new role for neurotrophin-3: involvement in the regulation of hair follicle regression (catagen). Am. J. Pathol. 153, 705–719 (1998).

    Article  Google Scholar 

  46. Ohsugi, M. et al. Expression and cell membrane localization of catenins during mouse preimplantation development. Dev. Dyn. 206, 391–402 (1996).

    Article  CAS  Google Scholar 

  47. Huber, O. et al. Nuclear localization of beta-catenin by interaction with transcription factor LEF-1. Mech. Dev. 59, 3– 10 (1996).

    Article  CAS  Google Scholar 

  48. Yamada, N. et al. Bone morphogenetic protein type IB receptor is progressively expressed in malignant glioma tumours. Br. J. Cancer 73, 624–629 (1996).

    Article  CAS  Google Scholar 

  49. Lindner, G. et al. Analysis of apoptosis during hair follicle regression (catagen) . Am. J. Pathol. 151, 1601– 1617 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  50. Paus, R., Foitzik, K., Welker, P., Bulfone-Paus, S. & Eichmüller, S. Transforming growth factor-beta receptor type I and type II expression during murine hair follicle development and cycling. J. Invest. Dermatol. 109, 518– 526 (1997).

    Article  CAS  Google Scholar 

  51. Handjiski, B., Eichmüller, S., Hofmann, U., Czarnetzki, B. M. & Paus, R. Alkaline phosphatase activity and localisation during the murine hair cycle. Br. J. Dermatol. 131, 303–310 (1994).

    Article  CAS  Google Scholar 

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Acknowledgements

We thank R. Pliet for technical assistance; R. Harland for providing the Noggin-producing cell line; A. Vortkamp and E. Chelkovnikova for the purification of Noggin protein; and O. Huber and K. Funa for supplying plasmids and antisera. This study was supported by a grant from the Deutsche Forschungsgemeinschaft to R.P. (Pa 345/8-2). Work in A.P.M.’s laboratory is supported by grants from the NIH.

Correspondence and requests for materials should be addressed to R.P. or V.A.B.

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Authors and Affiliations

  1. Department of Dermatology, Charité, Humboldt-University Berlin, Berlin, D-13344, Germany

    Vladimir A. Botchkarev, Natalia V. Botchkareva, Ling-Hong Chen & Gerd Lindner

  2. Department of Internal Medicine, University of Freiburg, Freiburg, D-79106, Germany

    Wera Roth & Christoph Peters

  3. Deutsches Rheumaforschungzentrum, Berlin, D-10117 , Germany

    Motonobu Nakamura, Wiebke Herzog & Roland Lauster

  4. Department of Dermatology, Kyoto University, Kyoto, 6068507,, Japan

    Motonobu Nakamura

  5. Molecular and Cellular Biology, Harvard University , Cambridge, 02138, Massachusetts, USA

    Jill A. McMahon & Andrew P. McMahon

  6. Department of Dermatology, University Hospital Eppendorf, University of Hamburg, Hamburg, D-20246, Germany

    Ralf Paus

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  1. Vladimir A. Botchkarev
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Correspondence to Ralf Paus.

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Botchkarev, V., Botchkareva, N., Roth, W. et al. Noggin is a mesenchymally derived stimulator of hair-follicle induction . Nat Cell Biol 1, 158–164 (1999). https://doi.org/10.1038/11078

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