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
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Buy this article
- Purchase on SpringerLink
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
![](https://media.springernature.com/m312/springer-static/image/art%3A10.1038%2Fncb1784/MediaObjects/41556_2008_Article_BFncb1784_Fig1_HTML.jpg)
![](https://media.springernature.com/m312/springer-static/image/art%3A10.1038%2Fncb1784/MediaObjects/41556_2008_Article_BFncb1784_Fig2_HTML.jpg)
![](https://media.springernature.com/m312/springer-static/image/art%3A10.1038%2Fncb1784/MediaObjects/41556_2008_Article_BFncb1784_Fig3_HTML.jpg)
![](https://media.springernature.com/m312/springer-static/image/art%3A10.1038%2Fncb1784/MediaObjects/41556_2008_Article_BFncb1784_Fig4_HTML.jpg)
![](https://media.springernature.com/m312/springer-static/image/art%3A10.1038%2Fncb1784/MediaObjects/41556_2008_Article_BFncb1784_Fig5_HTML.jpg)
![](https://media.springernature.com/m312/springer-static/image/art%3A10.1038%2Fncb1784/MediaObjects/41556_2008_Article_BFncb1784_Fig6_HTML.jpg)
![](https://media.springernature.com/m312/springer-static/image/art%3A10.1038%2Fncb1784/MediaObjects/41556_2008_Article_BFncb1784_Fig7_HTML.jpg)
![](https://media.springernature.com/m312/springer-static/image/art%3A10.1038%2Fncb1784/MediaObjects/41556_2008_Article_BFncb1784_Fig8_HTML.jpg)
Similar content being viewed by others
References
Zallen, J. A. Planar polarity and tissue morphogenesis. Cell 129, 1051–1063 (2007).
Seifert, J. R. & Mlodzik, M. Frizzled/PCP signalling: a conserved mechanism regulating cell polarity and directed motility. Nature Rev. Genet. 8, 126–138 (2007).
Jones, C. & Chen, P. Planar cell polarity signaling in vertebrates. Bioessays 29, 120–132 (2007).
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).
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).
Montcouquiol, M. et al. Identification of Vangl2 and Scrb1 as planar polarity genes in mammals. Nature 423, 173–177 (2003).
Wang, J. et al. Dishevelled genes mediate a conserved mammalian PCP pathway to regulate convergent extension during neurulation. Development 133, 1767–1778 (2006).
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).
Guo, N., Hawkins, C. & Nathans, J. Frizzled6 controls hair patterning in mice. Proc. Natl Acad. Sci. USA 101, 9277–9281 (2004).
Wang, Y., Badea, T. & Nathans, J. Order from disorder: Self-organization in mammalian hair patterning. Proc. Natl Acad. Sci. USA 103, 19800–19805 (2006).
Axelrod, J. D. & McNeill, H. Coupling planar cell polarity signaling to morphogenesis. ScientificWorld J. 2, 434–454 (2002).
Fuchs, E. Scratching the surface of skin development. Nature 445, 834–842 (2007).
Schmidt-Ullrich, R. & Paus, R. Molecular principles of hair follicle induction and morphogenesis. Bioessays 27, 247–261 (2005).
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).
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).
Magerl, M. et al. Patterns of proliferation and apoptosis during murine hair follicle morphogenesis. J. Invest. Dermatol. 116, 947–955 (2001).
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).
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).
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).
Harfe, B. D. et al. Evidence for an expansion-based temporal Shh gradient in specifying vertebrate digit identities. Cell 118, 517–528 (2004).
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).
Usui, T. et al. Flamingo, a seven-pass transmembrane cadherin, regulates planar cell polarity under the control of Frizzled. Cell 98, 585–595 (1999).
Strutt, D. I. Asymmetric localization of frizzled and the establishment of cell polarity in the Drosophila wing. Mol. Cell 7, 367–375 (2001).
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).
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).
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).
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).
St-Jacques, B. et al. Sonic hedgehog signaling is essential for hair development. Curr. Biol. 8, 1058–1068 (1998).
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).
Yang, A. et al. p63 is essential for regenerative proliferation in limb, craniofacial and epithelial development. Nature 398, 714–718 (1999).
Mills, A. A. et al. p63 is a p53 homologue required for limb and epidermal morphogenesis. Nature 398, 708–713 (1999).
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).
Lawrence, P. A., Struhl, G. & Casal, J. Planar cell polarity: one or two pathways? Nature Rev. Genet. 8, 555–563 (2007).
Taylor, J., Abramova, N., Charlton, J. & Adler, P. N. Van Gogh: a new Drosophila tissue polarity gene. Genetics 150, 199–210 (1998).
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).
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).
Chen, W. S. et al. Asymmetric homotypic interactions of the atypical cadherin flamingo mediate intercellular polarity signaling. Cell 133, 1093–1105 (2008).
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).
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).
Heisenberg, C. P. et al. Silberblick/Wnt11 mediates convergent extension movements during zebrafish gastrulation. Nature 405, 76–81 (2000).
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).
Qian, D. et al. Wnt5a functions in planar cell polarity regulation in mice. Dev. Biol. 306, 121–133 (2007).
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).
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).
Gho, M. & Schweisguth, F. Frizzled signalling controls orientation of asymmetric sense organ precursor cell divisions in Drosophila . Nature 393, 178–81 (1998).
Cooper, M. T. & Bray, S. J. Frizzled regulation of Notch signalling polarizes cell fate in the Drosophila eye. Nature 397, 526–530 (1999).
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).
Fanto, M. & Mlodzik, M. Asymmetric Notch activation specifies photoreceptors R3 and R4 and planar polarity in the Drosophila eye. Nature 397, 523–526 (1999).
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).
Tumbar, T. et al. Defining the epithelial stem cell niche in skin. Science 303, 359–363 (2004).
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
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
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
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/ncb1784
This article is cited by
-
Live imaging and conditional disruption of native PCP activity using endogenously tagged zebrafish sfGFP-Vangl2
Nature Communications (2022)
-
Genome-wide signatures of mammalian skin covering evolution
Science China Life Sciences (2021)
-
Somatic mutations in planar cell polarity genes in neural tissue from human fetuses with neural tube defects
Human Genetics (2020)
-
Counter-rotational cell flows drive morphological and cell fate asymmetries in mammalian hair follicles
Nature Cell Biology (2018)
-
Intracellular trafficking of planar cell polarity proteins
Frontiers in Biology (2018)