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Mitotic internalization of planar cell polarity proteins preserves tissue polarity

Nature Cell Biology volume 13, pages 893–902 (2011)Cite this article

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A Corrigendum to this article was published on 31 January 2017

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Abstract

Planar cell polarity (PCP) is the collective polarization of cells along the epithelial plane, a process best understood in the terminally differentiated Drosophila wing. Proliferative tissues such as mammalian skin also show PCP, but the mechanisms that preserve tissue polarity during proliferation are not understood. During mitosis, asymmetrically distributed PCP components risk mislocalization or unequal inheritance, which could have profound consequences for the long-range propagation of polarity. Here, we show that when mouse epidermal basal progenitors divide PCP components are selectively internalized into endosomes, which are inherited equally by daughter cells. Following mitosis, PCP proteins are recycled to the cell surface, where asymmetry is re-established by a process reliant on neighbouring PCP. A cytoplasmic dileucine motif governs mitotic internalization of atypical cadherin Celsr1, which recruits Vang2 and Fzd6 to endosomes. Moreover, embryos transgenic for a Celsr1 that cannot mitotically internalize exhibit perturbed hair-follicle angling, a hallmark of defective PCP. This underscores the physiological relevance and importance of this mechanism for regulating polarity during cell division.

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Figure 1: PCP components are selectively internalized in basal epidermal cells undergoing mitosis.
Figure 2: Mitotically internalized PCP components are inherited equally by both daughter cells and redelivered to the plasma membrane in a polarized manner.
Figure 3: On mitosis, PCP components are endocytosed by a clathrin-dependent mechanism and recycled to the plasma membrane.
Figure 4: Recruitment of Fzd6 and Vangl2 by Celsr1 to cell contacts during interphase and endocytic vesicles during mitosis.
Figure 5: Mitotic endocytosis of Celsr1 is mediated by a juxtamembrane dileucine motif.
Figure 6: Mitotic endocytosis of PCP components in basal stem cells is essential for PCP-mediated hair-follicle orientation in the skin.

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Change history

  • 12 January 2017

    In the version of this Article originally published, Supplementary Figure 4c portrayed normal mitotic internalization of a Celsr1ΔNSTTTTS–GFP mutant plasmid. Resequencing revealed an error in the sequence of this construct. Supplementary Figure 4c now shows representative images of keratinocytes expressing a construct harbouring the correct sequence of this mutant. The bona fide mutant shows reduced mitotic internalization compared with the wild-type control. This error does not affect the data presented in the main paper, nor does it change the major conclusions drawn. Additionally, in light of this error, all of the other sequences of constructs used in this study were verified. Supplementary Figure 4 has been corrected in the online versions of the Article and the text describing these data on page 897 has been changed accordingly.

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Acknowledgements

We thank N. Stokes for her assistance in the mouse facility, M. Montcouquoil for Vangl2 antibodies, and E. Vladar and J. Axelrod for sharing the lenti-Celsr1ΔN–GFP construct. We thank S. Simon laboratory members L. Macro and C. Atkinson for advice and constructs for TIRF imaging. We are grateful to S. Williams for retroviral vectors and technical assistance and to B. Short and members of the Fuchs laboratory for discussions and reading of the manuscript. We thank A. North and K. Thomas at the RU Bioimaging Resource Center for assistance with image acquisition, and the Comparative Biology Center (CBC) for their help in veterinary care. D.D. is the recipient of a K99 Award from the National Institutes of Health. E.F. is an investigator in the Howard Hughes Medical Institute. Work was supported by the Howard Hughes Medical Institute and the National Institutes of Health.

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  1. Howard Hughes Medical Institute, Laboratory of Mammalian Cell Biology & Development, The Rockefeller University, 1230 York Avenue, New York, New York 10065, Box 300, USA

    Danelle Devenport, Daniel Oristian, Evan Heller & Elaine Fuchs

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  1. Danelle Devenport
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Contributions

E.F. and D.D. designed experiments. D.D. carried out the experiments and analysed their raw data. D.O. carried out injections for generation of transgenic founder animals. E.H. carried out quantitative analyses of image data in Fig. 3. D.D. and E.F. wrote the paper.

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Correspondence to Elaine Fuchs.

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Devenport, D., Oristian, D., Heller, E. et al. Mitotic internalization of planar cell polarity proteins preserves tissue polarity. Nat Cell Biol 13, 893–902 (2011). https://doi.org/10.1038/ncb2284

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