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Deregulated expression of c-Myc depletes epidermal stem cells

Abstract

The β-catenin/TCF signaling pathway is essential for the maintenance of epithelial stem cells in the small intestine1. c-Myc a downstream target of β-catenin/TCF (ref. 2), can induce differentiation of epidermal stem cells in vitro3. To determine the role of c-Myc in epidermal stem cells in vivo, we have targeted expression of human MYC2 to the hair follicles and the basal layer of mouse epidermis using a keratin 14 vector (K14.MYC2). Adult K14.MYC2 mice gradually lose their hair and develop spontaneous ulcerated lesions due to a severe impairment in wound healing; their keratinocytes show impaired migration in response to wounding. The expression of β1 integrin, which is preferentially expressed in epidermal stem cells4 is unusually low in the epidermis of K14.MYC2 mice. Label-retaining analysis to identify epidermal stem cells reveals a 75% reduction in the number of stem cells in 3-month-old K14.MYC2 mice, compared with wildtype mice. We conclude that deregulated expression of c-Myc in stem cells reduces β1 integrin expression, which is essential to both keratinocyte migration and stem cell maintenance.

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Figure 1: Transgene expression and phenotype.
Figure 2: K14.MYC2 mice exhibit impairment in wound healing.
Figure 3: K14.MYC2 primary keratinocytes exhibit a defect in migration.
Figure 4: K14.MYC2 epidermis exhibits reduced staining for β1 integrin.
Figure 5: c-Myc represses transcription of β1 integrin.
Figure 6: K14.MYC2 epidermis exhibits a reduction in the number of stem cells.

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Acknowledgements

We would like to thank C.V. Dang for providing the human MYC cDNA and M. Rosenberg for providing the K14 vector. We would like to thank J. Bickenbach and M. Aumailley for experimental suggestions and interpretations, and P. Koch, S. Wojcik, C. Caulin, and M. Schneider for technical suggestions and comments on the manuscript. We also thank I. Arnold and F. Watt for communicating results prior to publication. This work was supported by National Institutes of Health Grants AR62228, CA52607, and HD25479 awarded to D.R. Roop, and CA79998 awarded to X.J. Wang. R.L. Waikel was supported by a Molecular Oncology Training Grant CA09197.

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Correspondence to Dennis R. Roop.

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Waikel, R., Kawachi, Y., Waikel, P. et al. Deregulated expression of c-Myc depletes epidermal stem cells. Nat Genet 28, 165–168 (2001). https://doi.org/10.1038/88889

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