The Role of IRF6 During Craniofacial Development

IRF6 在颅面发育过程中的作用

基本信息

批准号：
8307251
负责人：
Steven L Goudy
金额：
$ 12.07万
依托单位：
VANDERBILT UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-08-01 至 2013-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8307251
关键词：
Adhesions Affect Apoptosis Cardiac Cell Proliferation Cells Chimera organism Cleft Palate Complex Data Defect Development Environmental Risk Factor Epidermis Epithelial Epithelium Etiology Exhibits Genes Genetic Genetic Variation Goals Growth Growth Factor Growth and Development function Heterozygote Human In Situ In Situ Hybridization In Vitro Interferons Knock-out Knockout Mice Laboratories Lasers Lead Mandible Medial Mediating Mediator of activation protein Mesenchymal Mesenchymal Differentiation Mesenchyme Micrognathism Microscopy Modeling Mus Mutant Strains Mice Mutation Neural Crest Neural Crest Cell Oral Palate Pathway interactions Patients Phenotype Play Regulation Research Research Personnel Risk Role Signal Pathway Signal Transduction Signal Transduction Pathway Staging System Testing Time Van der Woude syndrome blastocyst cleft lip and palate craniofacial gene function gene interaction in vivo keratinocyte knockout animal laser capture microdissection mutant palatal fusion palatal shelves palatogenesis programs research study transcription factor

项目摘要

DESCRIPTION (provided by applicant): Isolated cleft lip and palate is a common congenital problem with a complex etiology. The objective of this research is to identify the function of genes critical to palatal formation. Genetic variation in Interferon Regulatory Factor 6 (IRF6) causes Van der Woude syndrome (VWS) and contributes 12% risk of isolated cleft lip and palate. The pathway containing Irf6 and its cellular role in orchestrating palatal development is not known. Mice deficient for Irf6 have cleft palate, micrognathia and oral adhesions. Mice deficient for either FgflO or Tbx1 have cleft palate and oral adhesions. Mutations in Tbx,1, FgflO, and Fgf8 in humans cause cleft lip and palate. Preliminary data from our laboratory suggests that FgflO expression in the palatal mesenchyme and Fgf8 expression in the palatal epithelium may be downstream targets for Irf6 activation. Furthermore, Irf6 in the craniofacial region may modulate expression of Tbx1 in the palate. Thus, we hypothesize that Irf6 functions in both a cell-autonomous manner to regulate epithelial differentiation and in a non-cell autonomous manner affecting mesenchymal differentiation and these functions are mediated in part through the Fgf signal transduction pathway and Tbx1. We propose to establish the role of Irf6 in palatogenesis and epithelial-mesenchymal signaling. We will evaluate apoptosis and proliferation in IrfSA- palatal shelves in-vivo and using in-vitro palatal cultures. Chimeric mice will be used to determine if Irf6 signals in a cell-autonomous fashion. To identify the role of Irf6 in palatal mesenchyme development we will use neural crest and non-neural crest specific ere mouse lines. In Aim 2 we will determine if FgflO is a downstream target of Irf6 signaling during palatal growth. We will evaluate changes in Irf6 and FgflO expression in Irf6 and FgflO null mice and test if there is a direct genetic interaction by creating double Fgf10/lrf6 heterozygous mice. In Aim 3 we will identify the gene(s) responsible for Irf6 signaling from the epithelium to the mesenchyme. We will investigate changes in expression of Tbx1 and Fgf8 in lrf6-\- mice. To test whether there is a direct genetic interaction, we will create double heterozygous Irf6/Tbx1 and Irf6/Fgf8 mice. The goal of this research is to understand the signaling pathway that includes IRF6, and how defects in this pathway lead to cleft lip and palate. We will use this information to examine potential gene-gene interactions in human cleft lip and palate patients.

描述（由申请人提供）：孤立性唇腭裂是一种常见的先天性问题，病因复杂。这项研究的目的是确定对腭形成至关重要的基因的功能。干扰素调节因子 6 (IRF6) 的遗传变异会导致范德沃德综合征 (VWS)，并导致 12% 的孤立性唇裂和腭裂风险。含有 Irf6 的通路及其在协调腭发育中的细胞作用尚不清楚。缺乏 Irf6 的小鼠会出现腭裂、小颌畸形和口腔粘连。缺乏 FgflO 或 Tbx1 的小鼠会出现腭裂和口腔粘连。人类 Tbx,1、FgflO 和 Fgf8 突变会导致唇裂和腭裂。我们实验室的初步数据表明，腭间充质中的 Fgf10 表达和腭上皮中的 Fgf8 表达可能是 Irf6 激活的下游靶标。此外，颅面部区域的 Irf6 可能调节上颚中 Tbx1 的表达。因此，我们假设 Irf6 以细胞自主方式调节上皮分化，并以非细胞自主方式影响间充质分化，并且这些功能部分通过 Fgf 信号转导途径和 Tbx1 介导。我们建议确定 Irf6 在腭发育和上皮间质信号传导中的作用。我们将使用体外腭培养物在体内评估 IrfSA-腭架的细胞凋亡和增殖。嵌合小鼠将用于确定 Irf6 是否以细胞自主方式发出信号。为了确定 Irf6 在腭间充质发育中的作用，我们将使用神经嵴和非神经嵴特异性 ere 小鼠品系。在目标 2 中，我们将确定 FgflO 是否是腭生长期间 Irf6 信号传导的下游靶标。我们将评估 Irf6 和 FgflO 缺失小鼠中 Irf6 和 FgflO 表达的变化，并通过创建双 Fgf10/lrf6 杂合小鼠来测试是否存在直接的遗传相互作用。在目标 3 中，我们将鉴定负责从上皮到间充质的 Irf6 信号传导的基因。我们将研究 lrf6-\- 小鼠中 Tbx1 和 Fgf8 表达的变化。为了测试是否存在直接的遗传相互作用，我们将创建双杂合 Irf6/Tbx1 和 Irf6/Fgf8 小鼠。这项研究的目的是了解包含 IRF6 的信号通路，以及该通路的缺陷如何导致唇裂和腭裂。我们将利用这些信息来检查人类唇裂和腭裂患者潜在的基因间相互作用。