Abstract
Stratification of the epidermis is essential for the barrier function of the skin. However, the molecular mechanisms governing epidermal stratification are not fully understood. Herein, we demonstrate that enkurin domain-containing protein 1 (ENKD1) contributes to epidermal stratification by modulating the cell-division orientation of basal keratinocytes. The epidermis of Enkd1 knockout mice is thinner than that of wild-type mice due to reduced generation of suprabasal cells from basal keratinocytes through asymmetric division. Depletion of ENKD1 impairs proper orientation of the mitotic spindle and delays mitotic progression in cultured cells. Mechanistic investigation further reveals that ENKD1 is a novel microtubule-binding protein that promotes the stability of astral microtubules. Introduction of the microtubule-binding domain of ENKD1 can largely rescue the spindle orientation defects in ENKD1-depleted cells. These findings establish ENKD1 as a critical regulator of astral microtubule stability and spindle orientation that stimulates epidermal stratification in mammalian cells.
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The authors declare that all data supporting the findings of this study are available within the paper in the main text or the Supplementary file.
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Acknowledgements
We are grateful to Drs. Huijie Zhao, Xueliang Zhu, and Rutao Cui for discussion. This work was supported by grants from the National Natural Science Foundation of China (31730050, 31871347, 32170829, 32070708, 32000490, and 32000870) and the National Key R&D Program of China (2017YFA0503502 and 2021YFA1101001).
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TZ and XW performed experiments and analyzed data; WX, XL, TS, SS, YL, DL and ML performed experiments; SX and JZ supervised the project and wrote the manuscript.
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All applicable institutional and/or national guidelines for the care and use of animals were followed. The use of mice was approved by the Animal Care and Use Committee of Shandong Normal University.
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Zhong, T., Wu, X., Xie, W. et al. ENKD1 promotes epidermal stratification by regulating spindle orientation in basal keratinocytes. Cell Death Differ 29, 1719–1729 (2022). https://doi.org/10.1038/s41418-022-00958-5
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DOI: https://doi.org/10.1038/s41418-022-00958-5
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