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

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.

A novel RIPK4–IRF6 connection is required to prevent epithelial fusions characteristic for popliteal pterygium syndromes

“…An abnormal skin architecture resembling that of RIPK4 − / − mice was also reported for IRF6 − / − mice, which have a defective skin barrier. 10,11 In WT mice, the skin barrier starts forming at E16 and is fully functional at E17. 18 Dye exclusion assays showed that toluidine blue and lucifer yellow penetrate E18.5 RIPK4 − / − skin but not RIPK4 +/+ skin (Figures 2a and b), indicating that a mature outside-in barrier is not formed in RIPK4 − / − skin.…”

“…The RIPK4 − / − mouse phenotype we observed is similar to that of the IRF6 − / − and the IRF6 R84C/R84C mice. 10,11 Moreover, similar to RIPK4 activity, IRF6 is also required for gastrulation in Danio rerio and X. laevis. 28 Until now, there is no evidence that functionally connects these two molecules.…”

“…31 Discontinuous cornified patches as in RIPK4 − / − skin has not been reported for IRF6 − / − mice, 10 but was observed in IRF6 +/R84C SFN +/Er mice that are compound heterozygous for a disease-related IRF6 mutant and for a mutation in the phosphoserine-threonine-binding protein stratifin. 11 This suggests that RIPK4 − / − mice phenocopy mice with reduced but not complete loss of IRF6 activity, or that RIPK4 integrates signals from multiple developmental cues. As reported for IRF6 − / − keratinocytes, 13 we were unable to induce differentiation of cultured RIPK4 − / − keratinocytes, which points to a cell autonomous defect.…”

“…Similar to RIPK4 − / − mice, transcription factor IRF6 − / − mice display fusion of the esophagus and defective epidermal differentiation. 10,11 In addition, IRF6 (interferon regulatory factor 6) and RIPK4 have been implicated in PPS. 8,9,12 We found that similar to IRF6 mutants, 10,11,13 RIPK4 − / − mice 1 have a defective skin barrier function and cleft palate, and RIPK4 − / − keratinocytes fail to differentiate in vitro.…”

“…10,11 In addition, IRF6 (interferon regulatory factor 6) and RIPK4 have been implicated in PPS. 8,9,12 We found that similar to IRF6 mutants, 10,11,13 RIPK4 − / − mice 1 have a defective skin barrier function and cleft palate, and RIPK4 − / − keratinocytes fail to differentiate in vitro. In Xenopus, we show that IRF6 controls RIPK4 expression and that RIPK4 can rescue developmental defects imposed by IRF6 dysfunction, thereby identifying a novel genetic interaction between IRF6 and RIPK4.…”