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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Autores principales:	Walid D. Fakhouri, Kareem Metwalli, Ali Naji, Sarah Bakhiet, Angela Quispe-Salcedo, Larissa Nitschke, Youssef A. Kousa, Brian C. Schutte
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/b269d22767a14456a5a09864fa5151e1
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spelling	oai:doaj.org-article:b269d22767a14456a5a09864fa5151e12021-12-02T15:05:43ZIntercellular Genetic Interaction Between Irf6 and Twist1 during Craniofacial Development10.1038/s41598-017-06310-z2045-2322https://doaj.org/article/b269d22767a14456a5a09864fa5151e12017-08-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-06310-zhttps://doaj.org/toc/2045-2322Abstract 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.Walid D. FakhouriKareem MetwalliAli NajiSarah BakhietAngela Quispe-SalcedoLarissa NitschkeYoussef A. KousaBrian C. SchutteNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-14 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q 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
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.
format	article
author	Walid D. Fakhouri Kareem Metwalli Ali Naji Sarah Bakhiet Angela Quispe-Salcedo Larissa Nitschke Youssef A. Kousa Brian C. Schutte
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 Portfolio
publishDate	2017
url	https://doaj.org/article/b269d22767a14456a5a09864fa5151e1
work_keys_str_mv	AT waliddfakhouri intercellulargeneticinteractionbetweenirf6andtwist1duringcraniofacialdevelopment AT kareemmetwalli intercellulargeneticinteractionbetweenirf6andtwist1duringcraniofacialdevelopment AT alinaji intercellulargeneticinteractionbetweenirf6andtwist1duringcraniofacialdevelopment AT sarahbakhiet intercellulargeneticinteractionbetweenirf6andtwist1duringcraniofacialdevelopment AT angelaquispesalcedo intercellulargeneticinteractionbetweenirf6andtwist1duringcraniofacialdevelopment AT larissanitschke intercellulargeneticinteractionbetweenirf6andtwist1duringcraniofacialdevelopment AT youssefakousa intercellulargeneticinteractionbetweenirf6andtwist1duringcraniofacialdevelopment AT briancschutte intercellulargeneticinteractionbetweenirf6andtwist1duringcraniofacialdevelopment
_version_	1718388726369878016

Intercellular Genetic Interaction Between Irf6 and Twist1 during Craniofacial Development

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