Irf6 is a key determinant of the keratinocyte proliferation-differentiation switch

Rebecca J Richardson, Jill Dixon, Saimon Malhotra, Matthew J Hardman, Lynnette Knowles, Ray P Boot-Handford, Paul Shore, Alan Whitmarsh, Michael J Dixon

Research output: Contribution to journalArticle (Academic Journal)peer-review

215 Citations (Scopus)

Abstract

The epidermis is a highly organized structure, the integrity of which is central to the protection of an organism. Development and subsequent maintenance of this tissue depends critically on the intricate balance between proliferation and differentiation of a resident stem cell population; however, the signals controlling the proliferation-differentiation switch in vivo remain elusive. Here, we show that mice carrying a homozygous missense mutation in interferon regulatory factor 6 (Irf6), the homolog of the gene mutated in the human congenital disorders Van der Woude syndrome and popliteal pterygium syndrome, have a hyperproliferative epidermis that fails to undergo terminal differentiation, resulting in soft tissue fusions. We further demonstrate that mice that are compound heterozygotes for mutations in Irf6 and the gene encoding the cell cycle regulator protein stratifin (Sfn; also known as 14-3-3sigma) show similar defects of keratinizing epithelia. Our results indicate that Irf6 is a key determinant of the keratinocyte proliferation-differentiation switch and that Irf6 and Sfn interact genetically in this process.

Original languageEnglish
Pages (from-to)1329-34
Number of pages6
JournalNature Genetics
Volume38
Issue number11
DOIs
Publication statusPublished - Nov 2006

Keywords

  • 14-3-3 Proteins
  • Animals
  • Cell Differentiation
  • Cell Proliferation
  • Cells, Cultured
  • Cleft Palate
  • Epidermis
  • Female
  • Genes, Switch
  • Humans
  • I-kappa B Kinase
  • Interferon Regulatory Factors
  • Keratinocytes
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Mouth Abnormalities
  • Mutation, Missense
  • Pregnancy

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