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Intercellular Genetic Interaction Between Irf6 and Twist1 during Craniofacial Development

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 mandi...

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Autores principales: Fakhouri, Walid D., Metwalli, Kareem, Naji, Ali, Bakhiet, Sarah, Quispe-Salcedo, Angela, Nitschke, Larissa, Kousa, Youssef A., Schutte, Brian C.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5540929/
https://www.ncbi.nlm.nih.gov/pubmed/28769044
http://dx.doi.org/10.1038/s41598-017-06310-z
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author Fakhouri, Walid D.
Metwalli, Kareem
Naji, Ali
Bakhiet, Sarah
Quispe-Salcedo, Angela
Nitschke, Larissa
Kousa, Youssef A.
Schutte, Brian C.
author_facet Fakhouri, Walid D.
Metwalli, Kareem
Naji, Ali
Bakhiet, Sarah
Quispe-Salcedo, Angela
Nitschke, Larissa
Kousa, Youssef A.
Schutte, Brian C.
author_sort Fakhouri, Walid D.
collection PubMed
description 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.
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spelling pubmed-55409292017-08-07 Intercellular Genetic Interaction Between Irf6 and Twist1 during Craniofacial Development Fakhouri, Walid D. Metwalli, Kareem Naji, Ali Bakhiet, Sarah Quispe-Salcedo, Angela Nitschke, Larissa Kousa, Youssef A. Schutte, Brian C. Sci Rep Article 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. Nature Publishing Group UK 2017-08-02 /pmc/articles/PMC5540929/ /pubmed/28769044 http://dx.doi.org/10.1038/s41598-017-06310-z Text en © The Author(s) 2017 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Fakhouri, Walid D.
Metwalli, Kareem
Naji, Ali
Bakhiet, Sarah
Quispe-Salcedo, Angela
Nitschke, Larissa
Kousa, Youssef A.
Schutte, Brian C.
Intercellular Genetic Interaction Between Irf6 and Twist1 during Craniofacial Development
title 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_short Intercellular Genetic Interaction Between Irf6 and Twist1 during Craniofacial Development
title_sort intercellular genetic interaction between irf6 and twist1 during craniofacial development
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5540929/
https://www.ncbi.nlm.nih.gov/pubmed/28769044
http://dx.doi.org/10.1038/s41598-017-06310-z
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