The Role of IRF6 During Craniofacial Development

IRF6 在颅面发育过程中的作用

• 批准号: 7530461
• 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
• 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/7530461
• 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; Polymerase Chain Reaction; 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

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）：孤立的嘴唇和pape是复杂的病因的常见先天性问题。这项研究的目的是确定对pal骨形成至关重要的基因的功能。干扰素调节因子6（IRF6）的遗传变异引起范德沃德综合征（VWS），并贡献了孤立的lip唇和pa的风险12％。尚不清楚包含IRF6的途径及其在编排pa骨发育中的细胞作用。缺乏IRF6的小鼠具有left裂，微处理和口服粘连。缺乏FGFLO或TBX1的小鼠的口腔粘附和口服粘合。人类TBX，1，FGFLO和FGF8的突变引起唇裂和pa。我们实验室的初步数据表明，pa质间充质中的FGFLO表达和palatal上皮中的FGF8表达可能是IRF6激活的下游靶标。此外，颅面区域中的IRF6可能会调节tbx1在口感中的表达。因此，我们假设IRF6以细胞自主的方式起作用，以调节上皮分化以及影响间质分化的非细胞自主性方式，并且这些功能通过FGF信号传递途径和TBX1的部分介导。我们建议确定IRF6在古质发生和上皮 - 间质信号传导中的作用。我们将评估IRFSA-PALATAL搁板中的凋亡和增殖，并使用体外palatal培养物。嵌合小鼠将用于确定IRF6信号是否以细胞自主方式。为了确定IRF6在palatal间充质发育中的作用，我们将使用神经rest和非神经rest特定的ERE小鼠系。在AIM 2中，我们将确定FGFLO是否是palatal生长过程中IRF6信号的下游目标。我们将评估IRF6和FGFLO NULL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AIM 3中，我们将确定负责IRF6信号从上皮到间质的基因。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，我们将创建双重杂合IRF6/TBX1和IRF6/FGF8小鼠。这项研究的目的是了解包括IRF6在内的信号传导途径，以及该途径中的缺陷如何导致唇裂和口感。我们将使用这些信息来检查人裂唇和口感患者中潜在的基因 - 基因相互作用。