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

• Published in: Nature communications Vol. 8; no. 1; p. 15397
• Main Authors: Xu, Mingang, Horrell, Jeremy, Snitow, Melinda, Cui, Jiawei, Gochnauer, Heather, Syrett, Camille M., Kallish, Staci, Seykora, John T., Liu, Fei, Gaillard, Dany, Katz, Jonathan P., Kaestner, Klaus H., Levin, Brooke, Mansfield, Corinne, Douglas, Jennifer E., Cowart, Beverly J., Tordoff, Michael, Liu, Fang, Zhu, Xuming, Barlow, Linda A., Rubin, Adam I., McGrath, John A., Morrisey, Edward E., Chu, Emily Y., Millar, Sarah E.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 07-06-2017; Nature Publishing Group; Nature Portfolio
• Subjects: 101/28; 14; 14/19; 14/35; 14/63; 38; 38/1; 38/15; 38/22; 38/77; 38/88; 38/90; 42; 45; 45/100; 45/41; 631/136/2441; 631/136/532; 631/532/2118/2438; 64; 64/110; 64/60; 82; 82/51; 82/80; 96; 96/44; 96/95; Amino Acid Sequence; Animals; Animals, Newborn; Axin Protein - metabolism; Base Sequence; beta Catenin - metabolism; Cell Differentiation; Cell growth; Cell Lineage; Cell Proliferation; Cell Self Renewal; Dermatology; Developmental biology; Ectodermal Dysplasia - genetics; Ectodermal Dysplasia - pathology; Embryonic Development; Epidermis - growth & development; Epidermis - pathology; Epidermis - ultrastructure; Epithelium - embryology; Epithelium - metabolism; Epithelium - ultrastructure; Female; Genetics; Hair Follicle - metabolism; Hair Follicle - pathology; Humanities and Social Sciences; Humans; Kruppel-Like Factor 4; Kruppel-Like Transcription Factors - metabolism; Loss of Function Mutation - genetics; Male; Medicine; Mice; Molar - embryology; Molar - metabolism; multidisciplinary; Mutation; Mutation - genetics; Nerve Tissue Proteins - genetics; Organ Specificity; Patients; Pedigree; Protein Binding; Science; Science (multidisciplinary); Stem cells; Stem Cells - metabolism; Taste; Teeth; Tongue; Transcription factors; Wnt Proteins - genetics; Wnt Signaling Pathway; United States > US; Texas; Pennsylvania
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/ncomms15397

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.
Human WNT10A mutations are associated with dental defects and adult onset ectodermal dysplasia. Xu
et al
. show that WNT10A-activated ß-catenin plays dual roles in adult epithelial progenitor proliferation and differentiation by complexing with KLF4 in differentiating, but not proliferating, cells.