Intercellular Genetic Interaction Between Irf6 and Twist1 during Craniofacial Development
Abstract 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...
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doaj-b269d22767a14456a5a09864fa5151e12020-12-08T00:35:27ZengNature Publishing GroupScientific Reports2045-23222017-08-017111410.1038/s41598-017-06310-zIntercellular Genetic Interaction Between Irf6 and Twist1 during Craniofacial DevelopmentWalid D. Fakhouri0Kareem Metwalli1Ali Naji2Sarah Bakhiet3Angela Quispe-Salcedo4Larissa Nitschke5Youssef A. Kousa6Brian C. Schutte7Center for Craniofacial Research, Department of Diagnostic and Biomedical Sciences, School of Dentistry, University of Texas Health Science Center at HoustonCenter for Craniofacial Research, Department of Diagnostic and Biomedical Sciences, School of Dentistry, University of Texas Health Science Center at HoustonCenter for Craniofacial Research, Department of Diagnostic and Biomedical Sciences, School of Dentistry, University of Texas Health Science Center at HoustonCenter for Craniofacial Research, Department of Diagnostic and Biomedical Sciences, School of Dentistry, University of Texas Health Science Center at HoustonCenter for Craniofacial Research, Department of Diagnostic and Biomedical Sciences, School of Dentistry, University of Texas Health Science Center at HoustonMicrobiology and Molecular Genetics, Michigan State UniversityDepartment of Biochemistry and Molecular Biology, Michigan State UniversityMicrobiology and Molecular Genetics, Michigan State UniversityAbstract 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.https://doi.org/10.1038/s41598-017-06310-z |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Walid D. Fakhouri Kareem Metwalli Ali Naji Sarah Bakhiet Angela Quispe-Salcedo Larissa Nitschke Youssef A. Kousa Brian C. Schutte |
spellingShingle |
Walid D. Fakhouri Kareem Metwalli Ali Naji Sarah Bakhiet Angela Quispe-Salcedo Larissa Nitschke Youssef A. Kousa Brian C. Schutte Intercellular Genetic Interaction Between Irf6 and Twist1 during Craniofacial Development Scientific Reports |
author_facet |
Walid D. Fakhouri Kareem Metwalli Ali Naji Sarah Bakhiet Angela Quispe-Salcedo Larissa Nitschke Youssef A. Kousa Brian C. Schutte |
author_sort |
Walid D. Fakhouri |
title |
Intercellular Genetic Interaction Between Irf6 and Twist1 during Craniofacial Development |
title_short |
Intercellular Genetic Interaction Between Irf6 and Twist1 during Craniofacial Development |
title_full |
Intercellular Genetic Interaction Between Irf6 and Twist1 during Craniofacial Development |
title_fullStr |
Intercellular Genetic Interaction Between Irf6 and Twist1 during Craniofacial Development |
title_full_unstemmed |
Intercellular Genetic Interaction Between Irf6 and Twist1 during Craniofacial Development |
title_sort |
intercellular genetic interaction between irf6 and twist1 during craniofacial development |
publisher |
Nature Publishing Group |
series |
Scientific Reports |
issn |
2045-2322 |
publishDate |
2017-08-01 |
description |
Abstract 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. |
url |
https://doi.org/10.1038/s41598-017-06310-z |
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