MOLECULAR BASIS OF TISSUE INTERACTIONS THAT REGULATE CRANIOFACIAL DEVELOPMENT

调节颅面发育的组织相互作用的分子基础

• 批准号: 7249157
• 负责人: RALPH S MARCUCIO
• 金额: $ 38.49万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-06-01 至 2011-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7249157
• 关键词: MOLECULAR; BASIS; TISSUE; INTERACTIONS; REGULATE

DESCRIPTION (provided by applicant): Development of the middle and upper face rely on signaling interactions among the forebrain, the neural crest mesenchyme, and the surface ectoderm. We have determined that signals derived from the forebrain control the formation of a signaling center (Frontonasal ectodermal zone; FEZ) in the surface ectoderm that regulates growth and patterning of the middle and upper face. Further, we demonstrated that disruptions to FEZ formation produced embryos that exhibited formes frustes of Holoprosencephaly (HPE). Our long term goal is to determine the underlying molecular mechanism(s) that regulate the establishment of the FEZ and to determine how signals derived from this signaling center regulate patterned growth of the middle and upper face. Cells within the FEZ express morphogens like Shh, Fibroblast growth factor 8 (Fgf8), and Bone morphogenetic proteins (Bmps). These molecules are ideal candidates for mediating function of the FEZ and are likely targets for teratogenic insults that produce malformations within this region of the head. We hypothesize that signaling by BMPs and SHH regulate induction of Shh expression in the ectoderm, and that together, Bmps, Shh, and Fgf8 regulate function of the FEZ. In our first Specific Aim we will assess whether BMP and/or SHH signaling are directly required within the ectodermal cells for induction of Shh expression in the FEZ, and we will assess the functional consequence of FEZ formation in the absence of BMP signaling. The objective of the second Specific Aim is to examine the role of the Bmps that are expressed within the FEZ using a tissue-specific, loss-of-function approach in avian embryos. Specifically, we will assess the morphological and molecular consequence of knocking-down Bmp expression. In our third Specific Aim we will assess the role of Fgf8 in establishing the FEZ, and the role of Fgf8 in mediating the function of this signaling center. We will use genetic approaches to ablate or reduce Fgf8 expression in the forebrain and ectoderm of mouse embryos and we will assess formation of the FEZ. Additionally, to distinguish between early and late roles of Fgf8 in FEZ function, we will characterize each FEZ in a novel chimeric system. Our results will contribute to the overall understanding of the epithelial-mesenchymal interactions that regulate development of the middle and upper face and will provide a basis to understand how defects in this region arise.

描述（由申请人提供）：中面的发展依赖于前脑，神经rest间充质和表面外胚层之间的信号相互作用。我们已经确定，从前脑控制的信号控制着调节中面的生长和模式的表面外胚层中信号转导中心的形成（额外外胚层; fez）。此外，我们证明了对FEZ形成的破坏产生的胚胎表现出形成型尸体脑（HPE）。我们的长期目标是确定调节FEZ建立的基本分子机制，并确定信号中心的信号如何调节中面的图案化生长。 FEZ内的细胞表达形态剂，例如SHH，成纤维细胞生长因子8（FGF8）和骨形态发生蛋白（BMP）。这些分子是FEZ介导功能的理想候选者，可能是致病性损伤的靶标，这些损伤会在头部的该区域内引起畸形。我们假设BMP和SHH信号调节了外胚层中SHH表达的诱导，并且BMP，SHH和FGF8一起调节了FEZ的功能。在我们的第一个特定目的中，我们将评估在外胚层细胞中直接需要BMP和/或SHH信号传导在FEZ中诱导SHH表达，我们将在没有BMP信号传导的情况下评估FEZ形成的功能后果。第二个特定目的的目的是检查使用组织特异性的，功能丧失方法在鸟类胚胎中表达的BMP的作用。具体而言，我们将评估敲击BMP表达的形态和分子后果。在我们的第三个特定目标中，我们将评估FGF8在建立FEZ中的作用，以及FGF8在中介该信号中心功能中的作用。我们将使用遗传学方法在小鼠胚胎的前脑和外胚层中消融或减少FGF8表达，我们将评估FEZ的形成。此外，为了区分FEZ功能中FGF8的早期和晚期角色，我们将在新型的嵌合系统中表征每个FEZ。我们的结果将有助于对调节中面和上面的发展的上皮间充质相互作用的整体理解，并将提供理解该区域中缺陷的基础。