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 PMID:28589954  

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 | Sarah E Millar
Nature communications | 2017

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.

Pubmed ID: 28589954

Associated grants

  • Agency: NIAMS NIH HHS, United States
    Id: P30 AR069619
  • Agency: NIDCD NIH HHS, United States
    Id: P30 DC011735
  • Agency: NIDCR NIH HHS, United States
    Id: R56 DE023100
  • Agency: NIAMS NIH HHS, United States
    Id: P30 AR069589
  • Agency: NIDCR NIH HHS, United States
    Id: R01 DE024570
  • Agency: NIGMS NIH HHS, United States
    Id: T32 GM007229
  • Agency: NIAMS NIH HHS, United States
    Id: R01 AR047709
  • Agency: NIAMS NIH HHS, United States
    Id: R37 AR047709
  • Agency: NICHD NIH HHS, United States
    Id: T32 HD083185
  • Agency: NIAMS NIH HHS, United States
    Id: T32 AR007465
  • Agency: NIDDK NIH HHS, United States
    Id: R01 DK069984
  • Agency: NIDCD NIH HHS, United States
    Id: R01 DC012383
  • Agency: NIAMS NIH HHS, United States
    Id: P30 AR057217
  • Agency: NIDCR NIH HHS, United States
    Id: R01 DE015342

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