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Cooperation between the transcription factors p63 and IRF6 is essential to prevent cleft palate in mice.
- Source :
-
The Journal of clinical investigation [J Clin Invest] 2010 May; Vol. 120 (5), pp. 1561-9. Date of Electronic Publication: 2010 Apr 26. - Publication Year :
- 2010
-
Abstract
- 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.
- Subjects :
- Animals
Binding Sites
Enhancer Elements, Genetic
Epistasis, Genetic
Genetic Variation
Heterozygote
Keratinocytes cytology
Mice
Models, Biological
Transcriptional Activation
Cleft Palate metabolism
Gene Expression Regulation, Developmental
Interferon Regulatory Factors genetics
Interferon Regulatory Factors metabolism
Mutation
Phosphoproteins genetics
Phosphoproteins metabolism
Trans-Activators genetics
Trans-Activators metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1558-8238
- Volume :
- 120
- Issue :
- 5
- Database :
- MEDLINE
- Journal :
- The Journal of clinical investigation
- Publication Type :
- Academic Journal
- Accession number :
- 20424327
- Full Text :
- https://doi.org/10.1172/JCI40266