Jagged-Notch and Fgf signaling: patterning the vertebrate upper face

Jagged-Notch 和 Fgf 信号：脊椎动物上表面的图案

• 批准号: 8123362
• 负责人: Elizabeth Zuniga-Sanchez
• 金额: $ 3.1万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-18 至 2013-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8123362
• 关键词: Alagille Syndrome; Animals; Apert-Crouzon syndrome; Cells; Congenital Abnormality; Craniofacial Abnormalities; Data; Defect; Development; Dorsal; Ectopic Expression; Embryo; Face; Fishes; Gene Expression; Genes; Genetic; Goals; Human; Image; Imaging Techniques; Linear Models; Link; Modeling; Molecular; Mutation; Neural Crest; Pathway interactions; Patients; Pattern; Reporter; Research Training; Resolution; Role; Signal Pathway; Signal Transduction; Skeleton; Specific qualifier value; Staging; Testing; Time; Transgenic Organisms; Transplantation; Work; Zebrafish; base; craniofacial; insight; jagged1 protein; mutant; notch protein; novel; receptor; research study; skeletal

DESCRIPTION (provided by applicant): Craniofacial abnormalities are the most common human birth defects, and yet little is known about the developmental basis that leads to mispatterning of the face. Several studies have Identified factors involved in patterning the lower (ventral) face; however, less is known about the dorsal (upper) face. In humans, mutations in Jagged and Notch have been linked to Alagille syndrome, whereas aberrant Fgf signaling results in Crouzon syndrome. As similar facial defects are observed in both Alagille and Crouzon, Notch and Fgf may be involved in a common pathway that patterns the facial skeleton. In this proposal, I investigate a novel role of Jagged-Notch and Fgf signaling in zebrafish involved in promoting dorsal facial identity. In my preliminary data, Jagged-Notch signaling promotes dorsal facial identity by repressing ventral gene expression in skeletal precursors; however, the molecular mechanism of how Notch promotes dorsal remains unknown. Thus in the first aim, I propose a model where dorsal facial identity is specified by a propagating Notch signaling wave that originates in the dorsal domain. Using a transgenic Notch reporter and high-resolution imaging, I will capture Notch activation in real time during patterning stages. In the second aim, I propose experiments that build on my initial findings that Fgf signaling also promotes dorsal identity. By using transgenic fish, in which Fgf signaling is upregulated or inhibited at specific times of development, I will determine if Fgf signaling uses similar molecular mechanisms as Notch to promote dorsal identity. In the third aim, I will test how Jagged-Notch and Fgf signaling pathways are integrated to actively promote dorsal facial identity. Here, I propose a linear and a parallel model of signal integration. In the linear model, Fgf signaling activates the Notch pathway by controlling jagib expression. In the parallel model, Fgf and Notch independently activate the same downstream targets involved in dorsal facial patterning. To test this, I will use combinations of mutants and transgenics with altered Notch and Fgf signaling to determine how these two pathways are integrated. The goal of this proposal is to investigate a novel role of Jagged-Notch and Fgf signaling in patterning the vertebrate upper face. As mutations in Jagged 1 and the Fgf receptor 2 have been linked to craniofacial defects in Alagille and Crouzon syndrome, my work in zebrafish will reveal the developmental basis by which disruption of these pathways results in facial defects in humans.

描述（由申请人提供）：颅面异常是人类最常见的先天缺陷，但对导致脸部误会的发育基础知之甚少。几项研究确定了涉及下部（腹侧）面对面的因素。但是，关于背面（上）面的知之甚少。在人类中，锯齿状和缺口的突变与阿拉吉尔综合征有关，而异常的FGF信号导致Crouzon综合征。由于在阿拉吉尔和克鲁赞中都观察到类似的面部缺陷，因此Notch和FGF可能参与了模拟面部骨骼的通用途径。在此提案中，我研究了锯齿状 - 诺奇和FGF信号传导在参与促进背部面部身份的斑马鱼中的新作用。在我的初步数据中，锯齿状的信号传导通过抑制骨骼前体中的腹侧基因表达来促进背部面部身份。然而，Notch如何促进背的分子机制仍然未知。因此，在第一个目标中，我提出了一个模型，其中背面面部身份是通过源自背侧结构域的传播Notch信号传导波来指定的。使用转基因Notch记者和高分辨率成像，我将在图案阶段实时捕获Notch激活。在第二个目标中，我提出的实验是基于我的初始发现，即FGF信号也促进了背面。通过使用转基因鱼，其中FGF信号在特定发育时期被上调或抑制，我将确定FGF信号传导是否使用类似的分子机制作为缺口来促进背认同。在第三个目标中，我将测试如何整合锯齿状的核电和FGF信号通路以积极促进背部面部身份。在这里，我提出了信号积分的线性和并行模型。在线性模型中，FGF信号传导通过控制Jagib表达来激活Notch途径。在平行模型中，FGF和Notch独立激活了背部面部图案中涉及的相同下游靶标。为了测试这一点，我将使用变化的Notch和FGF信号的突变体和转基因的组合来确定这两种途径的整合方式。该提案的目的是研究锯齿状 - 诺奇和FGF信号在对脊椎动物上面构图中的新作用。由于锯齿状1和FGF受体2的突变与阿拉吉尔和克鲁宗综合征中的颅面缺陷有关，我在斑马鱼中的工作将揭示出这些途径破坏这些途径导致人类面部缺陷的发育基础。