Abstract
The epidermis is a stratified squamous epithelium forming the barrier that excludes harmful microbes and retains body fluids. To perform these functions, proliferative basal cells in the innermost layer periodically detach from an underlying basement membrane of extracellular matrix, move outward and eventually die. Once suprabasal, cells stop dividing and enter a differentiation programme to form the barrier1. The mechanism of stratification is poorly understood. Although studies in vitro have led to the view that stratification occurs through the delamination and subsequent movement of epidermal cells2,3,4, most culture conditions favour keratinocytes that lack the polarity and cuboidal morphology of basal keratinocytes in tissue. These features could be important in considering an alternative mechanism, that stratification occurs through asymmetric cell divisions in which the mitotic spindle orients perpendicularly to the basement membrane5,6,7. Here we show that basal epidermal cells use their polarity to divide asymmetrically, generating a committed suprabasal cell and a proliferative basal cell. We further demonstrate that integrins and cadherins are essential for the apical localization of atypical protein kinase C, the Par3–LGN–Inscuteable complex and NuMA–dynactin to align the spindle.
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References
Fuchs, E. & Raghavan, S. Getting under the skin of epidermal morphogenesis. Nature Rev. Genet. 3, 199–209 (2002)
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)
Watt, F. M. Selective migration of terminally differentiating cells from the basal layer of cultured human epidermis. J. Cell Biol. 98, 16–21 (1984)
Watt, F. M. & Green, H. Stratification and terminal differentiation of cultured epidermal cells. Nature 295, 434–436 (1982)
Betschinger, J. & Knoblich, J. A. Dare to be different: asymmetric cell division in Drosophila, C. elegans and vertebrates. Curr. Biol. 14, R674–R685 (2004)
Cowan, C. R. & Hyman, A. A. Asymmetric cell division in C. elegans: cortical polarity and spindle positioning. Annu. Rev. Cell Dev. Biol. 20, 427–453 (2004)
Roegiers, F. & Jan, Y. N. Asymmetric cell division. Curr. Opin. Cell Biol. 16, 195–205 (2004)
Mills, A. A. et al. p63 is a p53 homologue required for limb and epidermal morphogenesis. Nature 398, 708–713 (1999)
Yang, A. et al. p63 is essential for regenerative proliferation in limb, craniofacial and epithelial development. Nature 398, 714–718 (1999)
Mariotti, A. et al. EGF-R signalling through Fyn kinase disrupts the function of integrin α6β4 at hemidesmosomes: role in epithelial cell migration and carcinoma invasion. J. Cell Biol. 155, 447–458 (2001)
Schlaepfer, D. D. & Hunter, T. Evidence for in vivo phosphorylation of the Grb2 SH2-domain binding site on focal adhesion kinase by Src-family protein-tyrosine kinases. Mol. Cell. Biol. 16, 5623–5633 (1996)
Tumbar, T. et al. Defining the epithelial stem cell niche in skin. Science 303, 359–363 (2004)
Kraut, R., Chia, W., Jan, L. Y., Jan, Y. N. & Knoblich, J. A. Role of inscuteable in orienting asymmetric cell divisions in Drosophila. Nature 383, 50–55 (1996)
Parmentier, M. L. et al. Rapsynoid/partner of inscuteable controls asymmetric division of larval neuroblasts in Drosophila. J. Neurosci. 20, RC84 (2000)
Schober, M., Schaefer, M. & Knoblich, J. A. Bazooka recruits Inscuteable to orient asymmetric cell divisions in Drosophila neuroblasts. Nature 402, 548–551 (1999)
Yu, F., Morin, X., Cai, Y., Yang, X. & Chia, W. Analysis of partner of inscuteable, a novel player of Drosophila asymmetric divisions, reveals two distinct steps in inscuteable apical localization. Cell 100, 399–409 (2000)
Du, Q. & Macara, I. G. Mammalian Pins is a conformational switch that links NuMA to heterotrimeric G proteins. Cell 119, 503–516 (2004)
Du, Q., Stukenberg, P. T. & Macara, I. G. A mammalian Partner of inscuteable binds NuMA and regulates mitotic spindle organization. Nature Cell Biol. 3, 1069–1075 (2001)
Gaglio, T., Saredi, A. & Compton, D. A. NuMA is required for the organization of microtubules into aster-like mitotic arrays. J. Cell Biol. 131, 693–708 (1995)
Kisurina-Evgenieva, O. et al. Multiple mechanisms regulate NuMA dynamics at spindle poles. J. Cell Sci. 117, 6391–6400 (2004)
Srinivasan, D. G., Fisk, R. M., Xu, H. & vam den Heuvel, S. A complex of Lin-5 and GPR proteins regulates G-protein signalling and spindle function in C. elegans. Genes Dev. 17, 1225–1239 (2003)
Price, C. M. & Pettijohn, D. E. Redistribution of the nuclear mitotic apparatus protein (NuMA) during mitosis and nuclear assembly. Properties of purified NuMA protein. Exp. Cell Res. 166, 95–317 (1986)
Grill, S. W., Howard, J., Schaffer, E., Stelzer, E. H. & Hyman, A. A. The distribution of active force generators controls mitotic spindle position. Science 301, 518–521 (2003)
Dowling, J., Yu, Q. C. & Fuchs, E. Beta4 integrin is required for hemidesmosome formation, cell adhesion and cell survival. J. Cell Biol. 134, 559–572 (1996)
van der Neut, R., Krimpenfort, P., Calafat, J., Niessen, C. M. & Sonnenberg, A. Epithelial detachment due to absence of hemidesmosomes in integrin β4 null mice. Nature Genet. 13, 366–369 (1996)
Brakebusch, C. et al. Skin and hair follicle integrity is crucially dependent on beta 1 integrin expression on keratinocytes. EMBO J. 19, 3990–4003 (2000)
Raghavan, S., Bauer, C., Mundschau, G., Li, Q. & Fuchs, E. Conditional ablation of β1 integrin in skin. Severe defects in epidermal proliferation, basement membrane formation, and hair follicle invagination. J. Cell Biol. 150, 1149–1160 (2000)
Vasioukhin, V., Bowers, E., Bauer, C., Degenstein, L. & Fuchs, E. Desmoplakin is essential in epidermal sheet formation. Nature Cell Biol. 3, 1076–1085 (2001)
Vasioukhin, V., Bauer, C., Degenstein, L., Wise, B. & Fuchs, E. Hyperproliferation and defects in epithelial polarity upon conditional ablation of alpha-catenin in skin. Cell 104, 605–617 (2001)
Lu, B., Roegiers, F., Jan, L. Y. & Jan, Y. N. Adherens junctions inhibit asymmetric division in the Drosophila epithelium. Nature 409, 522–525 (2001)
Kaushik, R., Yu, F., Chia, W., Yang, X. & Bahri, S. Subcellular localization of LGN during mitosis: evidence for its cortical localization in mitotic cell culture systems and its requirement for normal cell cycle progression. Mol. Biol. Cell 14, 3144–3155 (2003)
Acknowledgements
We thank M. Bornens and A. Mills for reagents; J. Fan for transgenic injections; L. Polak, E. Gonzales and LARC staff for care of the mice; H. Rhee for assistance with flow cytometry; members of the Fuchs laboratory for criticisms; and T. Kapoor for reagents and discussions. E.F. is an Investigator of the Howard Hughes Medical Institute. T.L. is a Jane Coffin Child postdoctoral fellow. This work was supported by a grant from the National Institutes of Health.
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Supplementary information
Supplementary Figure 1
This figure shows Northern and RT-PCR analysis of mouse inscuteable expression. It also contains a schematic comparison of Drosophila melanogaster, mouse, and human homologs. (PDF 91 kb)
Supplementary Figure 2
This figure demonstrates that alpha-catenin KO epidermis displays suprabasal integrin expression and loss of expression of the differentiation marker keratin-1. (PDF 207 kb)
Supplementary Figure Legends
This file contains legends for Supplementary Figures 1 and 2. (DOC 21 kb)
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Lechler, T., Fuchs, E. Asymmetric cell divisions promote stratification and differentiation of mammalian skin. Nature 437, 275–280 (2005). https://doi.org/10.1038/nature03922
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DOI: https://doi.org/10.1038/nature03922
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