Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Planar polarization in embryonic epidermis orchestrates global asymmetric morphogenesis of hair follicles

Abstract

Mammalian body hairs align along the anterior–posterior (A–P) axis and offer a striking but poorly understood example of global cell polarization, a phenomenon known as planar cell polarity (PCP). We have discovered that during embryogenesis, marked changes in cell shape and cytoskeletal polarization occur as nascent hair follicles become anteriorly angled, morphologically polarized and molecularly compartmentalized along the A–P axis. Hair follicle initiation coincides with asymmetric redistribution of Vangl2, Celsr1 and Fzd6 within the embryonic epidermal basal layer. Moreover, loss-of-function mutations in Vangl2 and Celsr1 show that they have an essential role in hair follicle polarization and orientation, which develop in part through non-autonomous mechanisms. Vangl2 and Celsr1 are both required for their planar localization in vivo, and physically associate in a complex in vitro. Finally, we provide in vitro evidence that homotypic intracellular interactions of Celsr1 are required to recruit Vangl2 and Fzd6 to sites of cell–cell contact.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Hair follicle angling is accompanied by polarized cell shape and cytoskeleton changes in anterior and posterior cells at the hair follicle-epidermal boundary.
Figure 2: A–P-polarized gene expression in embryonic hair follicles.
Figure 3: Anterior–posterior polarization of Vangl2 and Celsr1 in hair germs and the epidermal basal layer of embryonic skin.
Figure 4: PCP establishment occurs early and requires signals from the embryo but develops independently of stratification and hair follicle morphogenesis.
Figure 5: Genetic mutations in Vangl2 and Celsr1 result in loss of A–P alignment of hair follicles.
Figure 6: Loss of hair follicle asymmetry in PCP mutants.
Figure 7: Evidence for interactions between Celsr1 and Vangl2 in vivo and in vitro.
Figure 8: Fzd6 requires Vangl2 for its asymmetric localization in the epidermis and requires Celsr1 for it recruitment to cell contacts.

Similar content being viewed by others

References

  1. Zallen, J. A. Planar polarity and tissue morphogenesis. Cell 129, 1051–1063 (2007).

    Article  CAS  PubMed  Google Scholar 

  2. Seifert, J. R. & Mlodzik, M. Frizzled/PCP signalling: a conserved mechanism regulating cell polarity and directed motility. Nature Rev. Genet. 8, 126–138 (2007).

    Article  CAS  PubMed  Google Scholar 

  3. Jones, C. & Chen, P. Planar cell polarity signaling in vertebrates. Bioessays 29, 120–132 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Kibar, Z. et al. Ltap, a mammalian homolog of Drosophila Strabismus/Van Gogh, is altered in the mouse neural tube mutant Loop-tail. Nature Genet. 28, 25125–5 (2001).

    Article  Google Scholar 

  5. Curtin, J. A. et al. Mutation of Celsr1 disrupts planar polarity of inner ear hair cells and causes severe neural tube defects in the mouse. Curr. Biol. 13, 1129–1133 (2003).

    Article  CAS  PubMed  Google Scholar 

  6. Montcouquiol, M. et al. Identification of Vangl2 and Scrb1 as planar polarity genes in mammals. Nature 423, 173–177 (2003).

    Article  CAS  PubMed  Google Scholar 

  7. Wang, J. et al. Dishevelled genes mediate a conserved mammalian PCP pathway to regulate convergent extension during neurulation. Development 133, 1767–1778 (2006).

    Article  CAS  PubMed  Google Scholar 

  8. Wang, Y., Guo, N. & Nathans, J. The role of Frizzled3 and Frizzled6 in neural tube closure and in the planar polarity of inner-ear sensory hair cells. J. Neurosci. 26, 2147–2156 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Guo, N., Hawkins, C. & Nathans, J. Frizzled6 controls hair patterning in mice. Proc. Natl Acad. Sci. USA 101, 9277–9281 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Wang, Y., Badea, T. & Nathans, J. Order from disorder: Self-organization in mammalian hair patterning. Proc. Natl Acad. Sci. USA 103, 19800–19805 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Axelrod, J. D. & McNeill, H. Coupling planar cell polarity signaling to morphogenesis. ScientificWorld J. 2, 434–454 (2002).

    Article  Google Scholar 

  12. Fuchs, E. Scratching the surface of skin development. Nature 445, 834–842 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Schmidt-Ullrich, R. & Paus, R. Molecular principles of hair follicle induction and morphogenesis. Bioessays 27, 247–261 (2005).

    Article  CAS  PubMed  Google Scholar 

  14. Chodankar, R. et al. Shift of localized growth zones contributes to skin appendage morphogenesis: role of the Wnt/β-catenin pathway. J. Invest. Dermatol. 120, 20–6 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Vaezi, A., Bauer, C., Vasioukhin, V. & Fuchs, E. Actin cable dynamics and Rho/Rock orchestrate a polarized cytoskeletal architecture in the early steps of assembling a stratified epithelium. Dev. Cell 3, 367–381 (2002).

    Article  CAS  PubMed  Google Scholar 

  16. Magerl, M. et al. Patterns of proliferation and apoptosis during murine hair follicle morphogenesis. J. Invest. Dermatol. 116, 947–955 (2001).

    Article  CAS  PubMed  Google Scholar 

  17. 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  PubMed  Google Scholar 

  18. 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  PubMed  Google Scholar 

  19. Muller-Rover, S., Peters, E. J., Botchkarev, V. A., Panteleyev, A. & Paus, R. Distinct patterns of NCAM expression are associated with defined stages of murine hair follicle morphogenesis and regression. J. Histochem. Cytochem. 46, 1401–1410 (1998).

    Article  CAS  PubMed  Google Scholar 

  20. Harfe, B. D. et al. Evidence for an expansion-based temporal Shh gradient in specifying vertebrate digit identities. Cell 118, 517–528 (2004).

    Article  CAS  PubMed  Google Scholar 

  21. Bastock, R., Strutt, H. & Strutt, D. Strabismus is asymmetrically localised and binds to Prickle and Dishevelled during Drosophila planar polarity patterning. Development 130, 3007–3014 (2003).

    Article  CAS  PubMed  Google Scholar 

  22. Usui, T. et al. Flamingo, a seven-pass transmembrane cadherin, regulates planar cell polarity under the control of Frizzled. Cell 98, 585–595 (1999).

    Article  CAS  PubMed  Google Scholar 

  23. Strutt, D. I. Asymmetric localization of frizzled and the establishment of cell polarity in the Drosophila wing. Mol. Cell 7, 367–375 (2001).

    Article  CAS  PubMed  Google Scholar 

  24. Montcouquiol, M. et al. Asymmetric localization of Vangl2 and Fz3 indicate novel mechanisms for planar cell polarity in mammals. J. Neurosci. 26, 5265–5275 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Das, G., Reynolds-Kenneally, J. & Mlodzik, M. The atypical cadherin Flamingo links Frizzled and Notch signaling in planar polarity establishment in the Drosophila eye. Dev. Cell 2, 655–666 (2002).

    Article  CAS  PubMed  Google Scholar 

  26. Strutt, D., Johnson, R., Cooper, K. & Bray, S. Asymmetric localization of frizzled and the determination of notch-dependent cell fate in the Drosophila eye. Curr. Biol. 12, 813–824 (2002).

    Article  CAS  PubMed  Google Scholar 

  27. Bellaiche, Y., Beaudoin-Massiani, O., Stuttem, I. & Schweisguth, F. The planar cell polarity protein Strabismus promotes Pins anterior localization during asymmetric division of sensory organ precursor cells in Drosophila . Development 131, 469–478 (2004).

    Article  CAS  PubMed  Google Scholar 

  28. St-Jacques, B. et al. Sonic hedgehog signaling is essential for hair development. Curr. Biol. 8, 1058–1068 (1998).

    Article  CAS  PubMed  Google Scholar 

  29. Huelsken, J., Vogel, R., Erdmann, B., Cotsarelis, G. & Birchmeier, W. β-Catenin controls hair follicle morphogenesis and stem cell differentiation in the skin. Cell 105, 533–545 (2001).

    Article  CAS  PubMed  Google Scholar 

  30. Yang, A. et al. p63 is essential for regenerative proliferation in limb, craniofacial and epithelial development. Nature 398, 714–718 (1999).

    Article  CAS  PubMed  Google Scholar 

  31. Mills, A. A. et al. p63 is a p53 homologue required for limb and epidermal morphogenesis. Nature 398, 708–713 (1999).

    Article  CAS  PubMed  Google Scholar 

  32. Murdoch, J. N. et al. Circletail, a new mouse mutant with severe neural tube defects: chromosomal localization and interaction with the loop-tail mutation. Genomics 78, 55–63 (2001).

    Article  CAS  PubMed  Google Scholar 

  33. Lawrence, P. A., Struhl, G. & Casal, J. Planar cell polarity: one or two pathways? Nature Rev. Genet. 8, 555–563 (2007).

    Article  CAS  PubMed  Google Scholar 

  34. Taylor, J., Abramova, N., Charlton, J. & Adler, P. N. Van Gogh: a new Drosophila tissue polarity gene. Genetics 150, 199–210 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Adler, P. N., Taylor, J. & Charlton, J. The domineering non-autonomy of frizzled and van Gogh clones in the Drosophila wing is a consequence of a disruption in local signaling. Mech. Dev. 96, 197–207 (2000).

    Article  CAS  PubMed  Google Scholar 

  36. Das, G., Jenny, A., Klein, T. J., Eaton, S. & Mlodzik, M. Diego interacts with Prickle and Strabismus/Van Gogh to localize planar cell polarity complexes. Development 131, 4467–4476 (2004).

    Article  CAS  PubMed  Google Scholar 

  37. Chen, W. S. et al. Asymmetric homotypic interactions of the atypical cadherin flamingo mediate intercellular polarity signaling. Cell 133, 1093–1105 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Vasioukhin, V., Bauer, C., Yin, M. & Fuchs, E. Directed actin polymerization is the driving force for epithelial cell–cell adhesion. Cell 100, 209–219 (2000).

    Article  CAS  PubMed  Google Scholar 

  39. Lawrence, P. A., Casal, J. & Struhl, G. Towards a model of the organisation of planar polarity and pattern in the Drosophila abdomen. Development 129, 2749–2760 (2002).

    CAS  PubMed  Google Scholar 

  40. Heisenberg, C. P. et al. Silberblick/Wnt11 mediates convergent extension movements during zebrafish gastrulation. Nature 405, 76–81 (2000).

    Article  CAS  PubMed  Google Scholar 

  41. Tada, M. & Smith, J. C. Xwnt11 is a target of Xenopus Brachyury: regulation of gastrulation movements via Dishevelled, but not through the canonical Wnt pathway. Development 127, 2227–2238 (2000).

    CAS  PubMed  Google Scholar 

  42. Qian, D. et al. Wnt5a functions in planar cell polarity regulation in mice. Dev. Biol. 306, 121–133 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Reddy, S. et al. Characterization of Wnt gene expression in developing and postnatal hair follicles and identification of Wnt5a as a target of Sonic hedgehog in hair follicle morphogenesis. Mech. Dev. 107, 69–82 (2001).

    Article  CAS  PubMed  Google Scholar 

  44. Winter, C. G. et al. Drosophila Rho-associated kinase (Drok) links Frizzled-mediated planar cell polarity signaling to the actin cytoskeleton. Cell 105, 81–91 (2001).

    Article  CAS  PubMed  Google Scholar 

  45. Gho, M. & Schweisguth, F. Frizzled signalling controls orientation of asymmetric sense organ precursor cell divisions in Drosophila . Nature 393, 178–81 (1998).

    Article  CAS  PubMed  Google Scholar 

  46. Cooper, M. T. & Bray, S. J. Frizzled regulation of Notch signalling polarizes cell fate in the Drosophila eye. Nature 397, 526–530 (1999).

    Article  CAS  PubMed  Google Scholar 

  47. Tomlinson, A. & Struhl, G. Decoding vectorial information from a gradient: sequential roles of the receptors Frizzled and Notch in establishing planar polarity in the Drosophila eye. Development 126, 5725–5738 (1999).

    CAS  PubMed  Google Scholar 

  48. Fanto, M. & Mlodzik, M. Asymmetric Notch activation specifies photoreceptors R3 and R4 and planar polarity in the Drosophila eye. Nature 397, 523–526 (1999).

    Article  CAS  PubMed  Google Scholar 

  49. Chen, C. W., Jung, H. S., Jiang, T. X. & Chuong, C. M. Asymmetric expression of Notch/Delta/Serrate is associated with the anterior-posterior axis of feather buds. Dev. Biol. 188, 181–187 (1997).

    Article  CAS  PubMed  Google Scholar 

  50. Tumbar, T. et al. Defining the epithelial stem cell niche in skin. Science 303, 359–363 (2004).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank J. Murdoch, K. Anderson, M. Kelley, R. Rachel, B. Lake and C. Tabin, for mice and embryos; M. Montcouquiol, S. Sokol and M. Takeiechi for antibodies and reagents; L. Polak, N. Stokes and LARC staff for care and breeding of mice; J. Zallen, S. Sokol and A. vandenBerg for helpful discussions; Alison North and Rockefeller's Bioimaging Resource Centre for assistance with image acquisition and analysis; J. Racelis and A. Firland-Schill for experimental assistance; B. Short, V. Horsley and J. Nowak for advice and critical reading of the manuscript. D.D. is a Ruth L. Kirschstein NRSA postdoctoral fellow. This work was supported by a grant from the National Institutes of Health (R01 AR27883). E.F. is an Investigator of the Howard Hughes Medical Institute.

Author information

Authors and Affiliations

Authors

Contributions

D.D. designed, performed and analysed the experiments and wrote the manuscript. E.F. supervised the project and wrote the manuscript.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Information

Supplementary Information (PDF 1063 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Devenport, D., Fuchs, E. Planar polarization in embryonic epidermis orchestrates global asymmetric morphogenesis of hair follicles. Nat Cell Biol 10, 1257–1268 (2008). https://doi.org/10.1038/ncb1784

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ncb1784

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing