Irf6 is a key determinant of the keratinocyte proliferation-differentiation switch.
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.
Richardson
Rebecca J
RJ
Faculty of Life Sciences, University of Manchester, Oxford Road, Manchester M13 9PT, UK.
Dixon
Jill
J
Malhotra
Saimon
S
Hardman
Matthew J
MJ
Knowles
Lynnette
L
Boot-Handford
Ray P
RP
Shore
Paul
P
Whitmarsh
Alan
A
Dixon
Michael J
MJ
D048948:14-3-3 Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D000818:Animals; D002454:Cell Differentiation / Q000502:physiology*; D049109:Cell Proliferation; D002478:Cells, Cultured; D002972:Cleft Palate / Q000235:genetics; D004817:Epidermis / Q000196:embryology; D005260:Female; D005812:Genes, Switch / Q000502:physiology; D006801:Humans; D051550:I-kappa B Kinase / Q000235:genetics / Q000502:physiology; D050835:Interferon Regulatory Factors / Q000235:genetics / Q000502:physiology*; D015603:Keratinocytes / Q000166:cytology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009056:Mouth Abnormalities / Q000235:genetics; D020125:Mutation, Missense; D011247:Pregnancy
D048948:14-3-3 Proteins; C109803:IRF6 protein, human; D050835:Interferon Regulatory Factors; C499130:Sfn protein, mouse; C496564:Chuk protein, mouse; D051550:I-kappa B Kinase