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Interferon Regulatory Factor 6 ( IRF6 ) and  TWIST1  are transcription factors necessary for craniofacial development. Human genetic studies showed that mutations in  IRF6  lead to cleft lip and palate and mandibular abnormalities. In the mouse, we found that loss of  Irf6  causes craniosynostosis and mandibular hypoplasia. Similarly, mutations in  TWIST1  cause craniosynostosis, mandibular hypoplasia and cleft palate. Based on this phenotypic overlap, we asked if  Irf6  and  Twist1  interact genetically during craniofacial formation. While single heterozygous mice are normal, double heterozygous embryos ( Irf6   + /−  ;  Twist1   + /−  ) can have severe mandibular hypoplasia that leads to agnathia and cleft palate at birth. Analysis of spatiotemporal expression showed that  Irf6  and  Twist1  are found in different cell types. Consistent with the intercellular interaction, we found reduced expression of Endothelin1 (EDN1) in mandible and transcription factors that are critical for mandibular patterning including DLX5, DLX6 and HAND2, were also reduced in mesenchymal cells. Treatment of mandibular explants with exogenous EDN1 peptides partially rescued abnormalities in Meckel’s cartilage. In addition, partial rescue was observed when double heterozygous embryos also carried a null allele of  p53 . Considering that variants in  IRF6  and  TWIST1  contribute to human craniofacial defects, this gene-gene interaction may have implications on craniofacial disorders.

Intercellular Genetic Interaction Between Irf6 and Twist1 during Craniofacial Development