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: 8288026
• 负责人: Elizabeth Zuniga-Sanchez
• 金额: $ 0.26万
• 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 2012-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8288026
• 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）：颅面畸形是最常见的人类出生缺陷，但人们对导致面部畸形的发育基础知之甚少。几项研究已经确定了与下（腹）面图案有关的因素；然而，人们对背（上）面知之甚少。在人类中，Jagged 和 Notch 突变与 Alagille 综合征有关，而 Fgf 信号传导异常则导致 Crouzon 综合征。由于在 Alagille 和 Crouzon 中都观察到了类似的面部缺陷，Notch 和 Fgf 可能参与了塑造面部骨骼的共同途径。在本提案中，我研究了斑马鱼中 Jagged-Notch 和 Fgf 信号传导在促进背部面部身份方面的新作用。在我的初步数据中，锯齿状缺口信号传导通过抑制骨骼前体中的腹侧基因表达来促进背侧面部特征；然而，Notch 如何促进背侧运动的分子机制仍不清楚。因此，在第一个目标中，我提出了一个模型，其中背部面部身份由源自背部区域的传播的 Notch 信号波指定。使用转基因Notch报告基因和高分辨率成像，我将在图案化阶段实时捕获Notch激活。在第二个目标中，我提出了基于我最初发现的实验，即 Fgf 信号传导也促进背侧身份。通过使用转基因鱼，其中 Fgf 信号在特定的发育时期被上调或抑制，我将确定 Fgf 信号是否使用与 Notch 类似的分子机制来促进背侧身份。在第三个目标中，我将测试 Jagged-Notch 和 Fgf 信号通路如何整合以积极促进背侧面部识别。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 信号通过控制 jagib 表达来激活 Notch 通路。在并行模型中，Fgf 和 Notch 独立激活参与背侧面部图案的相同下游目标。为了测试这一点，我将使用突变体和转基因与改变的 Notch 和 Fgf 信号传导的组合来确定这两种途径是如何整合的。该提案的目标是研究锯齿状缺口和 Fgf 信号在脊椎动物上面部图案化中的新作用。由于 Jagged 1 和 Fgf 受体 2 的突变与阿拉吉尔和克鲁宗综合征的颅面缺陷有关，我在斑马鱼中的研究将揭示这些通路的破坏导致人类面部缺陷的发育基础。