WNT10A mutation causes ectodermal dysplasia by impairing progenitor cell proliferation and KLF4-mediated differentiation

Nat Commun. 2017 Jun 7;8:15397. doi: 10.1038/ncomms15397.

Mingang Xu ¹, Jeremy Horrell ¹, Melinda Snitow ², Jiawei Cui ¹, Heather Gochnauer ¹, Camille M Syrett ¹, Staci Kallish ², John T Seykora ¹, Fei Liu ³, Dany Gaillard ⁴, Jonathan P Katz ², Klaus H Kaestner ⁵, Brooke Levin ⁶, Corinne Mansfield ⁷, Jennifer E Douglas ⁷, Beverly J Cowart ⁷, Michael Tordoff ⁷, Fang Liu ¹, Xuming Zhu ¹, Linda A Barlow ⁴, Adam I Rubin ¹, John A McGrath ⁸, Edward E Morrisey ², Emily Y Chu ¹, Sarah E Millar ¹ ⁹

Affiliations

1 Department of Dermatology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
2 Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
3 Molecular &Cellular Medicine Department, Texas A&M University Health Science Center, College Station, Texas 77843, USA.
4 Department of Cell and Developmental Biology, and Rocky Mountain Taste and Smell Center, University of Colorado School of Medicine, Aurora, Colorado 80045, USA.
5 Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
6 William G. Rohrer Cancer Genetics Program, M.D. Anderson Cancer Center at Cooper, Camden, New Jersey 08103, USA.
7 Monell Chemical Senses Center, Philadelphia, Pennsylvania 19104, USA.
8 Department of Medical and Molecular Genetics, St John's Institute of Dermatology, King's College London, London SE1 9RT, UK.
9 Department of Cell and Developmental Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.

PMID: 28589954 DOI: 10.1038/ncomms15397

Abstract

Human WNT10A mutations are associated with developmental tooth abnormalities and adolescent onset of a broad range of ectodermal defects. Here we show that β-catenin pathway activity and adult epithelial progenitor proliferation are reduced in the absence of WNT10A, and identify Wnt-active self-renewing stem cells in affected tissues including hair follicles, sebaceous glands, taste buds, nails and sweat ducts. Human and mouse WNT10A mutant palmoplantar and tongue epithelia also display specific differentiation defects that are mimicked by loss of the transcription factor KLF4. We find that β-catenin interacts directly with region-specific LEF/TCF factors, and with KLF4 in differentiating, but not proliferating, cells to promote expression of specialized keratins required for normal tissue structure and integrity. Our data identify WNT10A as a critical ligand controlling adult epithelial proliferation and region-specific differentiation, and suggest downstream β-catenin pathway activation as a potential approach to ameliorate regenerative defects in WNT10A patients.

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