Intercellular Genetic Interaction Between Irf6 and Twist1 during Craniofacial Development.
Intercellular Genetic Interaction Between Irf6 and Twist1 during Craniofacial Development.
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DOI：
10.1038/s41598-017-06310-z
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发表时间：
2017-08-02
影响因子：
4.6
通讯作者：
Schutte BC
中科院分区：
文献类型：
--
作者：
Fakhouri WD;Metwalli K;Naji A;Bakhiet S;Quispe-Salcedo A;Nitschke L;Kousa YA;Schutte BC
干扰素调节因子6 （IRF6）和TWIST1是颅面发育所必需的转录因子。人类遗传学研究表明，IRF6突变导致唇腭裂和下颌畸形。在小鼠中，我们发现Irf6的缺失导致颅缝闭合和下颌发育不全。同样，TWIST1基因的突变会导致颅缝闭锁、下颌发育不全和腭裂。基于这种表型重叠，我们询问Irf6和Twist1在颅面形成过程中是否在遗传上相互作用。虽然单杂合小鼠是正常的，但双杂合胚胎（Irf6 +/−;Twist1 +/−）可能会出现严重的下颌发育不全，导致出生时的畸形和腭裂。时空表达分析表明，Irf6和Twist1存在于不同的细胞类型中。与细胞间相互作用一致，我们发现内皮素1 （EDN1）在下颌骨中的表达减少，而对下颌模式至关重要的转录因子，包括DLX5、DLX6和HAND2，在间质细胞中也减少了。用外源性EDN1肽治疗下颌外植体部分修复梅克尔软骨异常。此外，当双杂合胚胎也携带p53的空等位基因时，观察到部分挽救。考虑到IRF6和TWIST1的变异有助于人类颅面缺陷，这种基因-基因相互作用可能对颅面疾病有影响。
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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DOI：
10.14740/jocmr1905w
发表时间：
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期刊：
Journal of clinical medicine research
影响因子：
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