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.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Animals, Newborn
  • Axin Protein / metabolism
  • Base Sequence
  • Cell Differentiation*
  • Cell Lineage
  • Cell Proliferation
  • Cell Self Renewal
  • Ectodermal Dysplasia / genetics*
  • Ectodermal Dysplasia / pathology*
  • Embryonic Development
  • Epidermis / growth & development
  • Epidermis / pathology
  • Epidermis / ultrastructure
  • Epithelium / embryology
  • Epithelium / metabolism
  • Epithelium / ultrastructure
  • Female
  • Hair Follicle / metabolism
  • Hair Follicle / pathology
  • Humans
  • Kruppel-Like Transcription Factors / metabolism*
  • Loss of Function Mutation / genetics
  • Male
  • Mice
  • Molar / embryology
  • Molar / metabolism
  • Mutation / genetics*
  • Nerve Tissue Proteins / genetics*
  • Organ Specificity
  • Pedigree
  • Protein Binding
  • Stem Cells / metabolism*
  • Wnt Proteins / genetics*
  • Wnt Signaling Pathway
  • beta Catenin / metabolism

Substances

  • Axin Protein
  • Axin2 protein, mouse
  • GKLF protein
  • Kruppel-Like Transcription Factors
  • Nerve Tissue Proteins
  • WNT10A protein, human
  • Wnt Proteins
  • Wnt10a protein, mouse
  • beta Catenin