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Asymmetric cell divisions promote stratification and differentiation of mammalian skin

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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Figure 1: Asymmetric cell divisions govern stratification and differentiation during epidermal development.
Figure 2: Mitotic apical localization of a mInsc–LGN–Par3 complex.
Figure 3: Polarized mitotic localization of NuMA and dynactin.
Figure 4: Cadherin and integrin requirements for LGN–NuMA localization and spindle orientation.

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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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Correspondence to Elaine Fuchs.

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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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