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Dual requirements for WNT10A in proliferation and KLF4-mediated differentiation underlie ectodermal dysplasia

Research output: Contribution to journalArticle

Mingang Zu, 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 & 5 more Adam I. Rubin, John A. McGrath, Edward E. Morrisey, Emily Y. Chu, Sarah E. Millar

Original languageEnglish
JournalNature Communications
Volume8
Early online date7 Jun 2017
DOIs
Publication statusE-pub ahead of print - 7 Jun 2017

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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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