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）：中面部和上面部的发育依赖于前脑、神经嵴间充质和表面外胚层之间的信号相互作用。我们已经确定，来自前脑的信号控制表面外胚层中信号中心（额鼻外胚层区；FEZ）的形成，调节中面部和上面部的生长和图案。此外，我们证明，FEZ 形成的破坏产生了表现出前脑无裂畸形 (HPE) 的胚胎。我们的长期目标是确定调节 FEZ 建立的潜在分子机制，并确定来自该信号中心的信号如何调节中部和上部面的图案化生长。 FEZ 内的细胞表达 Shh、成纤维细胞生长因子 8 (Fgf8) 和骨形态发生蛋白 (Bmps) 等形态发生素。这些分子是调节 FEZ 功能的理想候选分子，并且可能是导致该头部区域内产生畸形的致畸损伤的目标。我们假设 BMP 和 SHH 的信号传导调节外胚层中 Shh 表达的诱导，并且 Bmp、Shh 和 Fgf8 共同调节 FEZ 的功能。在我们的第一个具体目标中，我们将评估外胚层细胞内是否直接需要 BMP 和/或 SHH 信号传导来诱导 FEZ 中的 Shh 表达，并且我们将评估在缺乏 BMP 信号传导的情况下 FEZ 形成的功能后果。第二个具体目标的目的是使用组织特异性、功能丧失方法在禽类胚胎中检查 FEZ 内表达的 Bmp 的作用。具体来说，我们将评估敲低 Bmp 表达的形态学和分子结果。在我们的第三个具体目标中，我们将评估 Fgf8 在建立 FEZ 中的作用，以及 Fgf8 在介导该信号中心功能中的作用。我们将使用遗传方法消除或减少小鼠胚胎前脑和外胚层中 Fgf8 的表达，并评估 FEZ 的形成。此外，为了区分 Fgf8 在 FEZ 功能中的早期和晚期作用，我们将表征新型嵌合系统中的每个 FEZ。我们的结果将有助于全面了解调节面部中部和上部发育的上皮间质相互作用，并将为了解该区域的缺陷如何产生提供基础。