Cooperation between the transcription factors p63 and IRF6 is essential to prevent cleft palate in mice.
Cleft palate is a common congenital disorder that affects up to 1 in 2,500 live human births and results in considerable morbidity to affected individuals and their families. The etiology of cleft palate is complex, with both genetic and environmental factors implicated. Mutations in the transcription factor-encoding genes p63 and interferon regulatory factor 6 (IRF6) have individually been identified as causes of cleft palate; however, a relationship between the key transcription factors p63 and IRF6 has not been determined. Here, we used both mouse models and human primary keratinocytes from patients with cleft palate to demonstrate that IRF6 and p63 interact epistatically during development of the secondary palate. Mice simultaneously carrying a heterozygous deletion of p63 and the Irf6 knockin mutation R84C, which causes cleft palate in humans, displayed ectodermal abnormalities that led to cleft palate. Furthermore, we showed that p63 transactivated IRF6 by binding to an upstream enhancer element; genetic variation within this enhancer element is associated with increased susceptibility to cleft lip. Our findings therefore identify p63 as a key regulatory molecule during palate development and provide a mechanism for the cooperative role of p63 and IRF6 in orofacial development in mice and humans.
Thomason
Helen A
HA
Faculty of Medical and Human Sciences, Manchester Academic Health Sciences Centre, University of Manchester, Manchester, United Kingdom.
Zhou
Huiqing
H
Kouwenhoven
Evelyn N
EN
Dotto
Gian-Paolo
GP
Restivo
Gaia
G
Nguyen
Bach-Cuc
BC
Little
Hayley
H
Dixon
Michael J
MJ
van Bokhoven
Hans
H
Dixon
Jill
J
D000818:Animals; D001665:Binding Sites; D002972:Cleft Palate / Q000378:metabolism*; D004742:Enhancer Elements, Genetic; D004843:Epistasis, Genetic; D018507:Gene Expression Regulation, Developmental; D014644:Genetic Variation; D006579:Heterozygote; D050835:Interferon Regulatory Factors / Q000235:genetics* / Q000378:metabolism*; D015603:Keratinocytes / Q000166:cytology; D051379:Mice; D008954:Models, Biological; D009154:Mutation; D010750:Phosphoproteins / Q000235:genetics* / Q000378:metabolism*; D015534:Trans-Activators / Q000235:genetics* / Q000378:metabolism*; D015533:Transcriptional Activation
C528250:IRF6 protein, mouse; D050835:Interferon Regulatory Factors; D010750:Phosphoproteins; D015534:Trans-Activators; C486419:Trp63 protein, mouse