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

Mingang Xu, Jeremy Horrell, Melinda Snitow, Jiawei Cui, Heather Gochnauer, Camille M. Syrett, Staci Kallish, John T. Seykora, Fei Liu, Dany Gaillard, Jonathan P. Katz, Klaus H. Kaestner, Brooke Levin, Corinne Mansfield, Jennifer E. Douglas, Beverly J. Cowart, Michael Tordoff, Fang Liu, Xuming Zhu, Linda A. Barlow, Adam I. Rubin, John A. McGrath, Edward E. Morrisey, Emily Y. Chu and Sarah E. Millar ()
Additional contact information
Mingang Xu: Perelman School of Medicine, University of Pennsylvania
Jeremy Horrell: Perelman School of Medicine, University of Pennsylvania
Melinda Snitow: Perelman School of Medicine, University of Pennsylvania
Jiawei Cui: Perelman School of Medicine, University of Pennsylvania
Heather Gochnauer: Perelman School of Medicine, University of Pennsylvania
Camille M. Syrett: Perelman School of Medicine, University of Pennsylvania
Staci Kallish: Perelman School of Medicine, University of Pennsylvania
John T. Seykora: Perelman School of Medicine, University of Pennsylvania
Fei Liu: Texas A&M University Health Science Center
Dany Gaillard: and Rocky Mountain Taste and Smell Center, University of Colorado School of Medicine
Jonathan P. Katz: Perelman School of Medicine, University of Pennsylvania
Klaus H. Kaestner: Perelman School of Medicine, University of Pennsylvania
Brooke Levin: William G. Rohrer Cancer Genetics Program, M.D. Anderson Cancer Center at Cooper
Corinne Mansfield: Monell Chemical Senses Center
Jennifer E. Douglas: Monell Chemical Senses Center
Beverly J. Cowart: Monell Chemical Senses Center
Michael Tordoff: Monell Chemical Senses Center
Fang Liu: Perelman School of Medicine, University of Pennsylvania
Xuming Zhu: Perelman School of Medicine, University of Pennsylvania
Linda A. Barlow: and Rocky Mountain Taste and Smell Center, University of Colorado School of Medicine
Adam I. Rubin: Perelman School of Medicine, University of Pennsylvania
John A. McGrath: St John’s Institute of Dermatology, King’s College London
Edward E. Morrisey: Perelman School of Medicine, University of Pennsylvania
Emily Y. Chu: Perelman School of Medicine, University of Pennsylvania
Sarah E. Millar: Perelman School of Medicine, University of Pennsylvania

Nature Communications, 2017, vol. 8, issue 1, 1-21

Abstract: 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.

Date: 2017
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DOI: 10.1038/ncomms15397

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