Epithelial-mesenchymal interactions in facial patterning

面部图案中的上皮-间质相互作用

• 批准号: 8122258
• 负责人: Gage D Crump
• 金额: $ 38.7万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-01 至 2013-05-05
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8122258
• 关键词: Ablation; Address; Binding; Birds; Branchial arch structure; Cartilage; Cell Therapy; Cells; Cellular biology; Cephalic; Characteristics; Cloning; Code; Congenital Abnormality; DNA Sequence Rearrangement; Development; Diagnosis; Disease; Dorsal; Ectoderm; Embryo; Endoderm; Epithelial; Epithelium; Face; First Pharyngeal Arch; Genes; Genetic; Goals; Human; Image; Intrinsic factor; Knowledge; Lasers; Lateral; Lead; Maps; Medial; Mesenchymal; Mesenchyme; Modeling; Molecular; Morphogenesis; Morphology; Natural regeneration; Neural Crest Cell; Pathway interactions; Pattern; Physical condensation; Positioning Attribute; Prevention; Repression; Research; Research Personnel; Resolution; Role; Shapes; Signal Transduction; Signaling Molecule; Skeletal Development; Skeleton; Specific qualifier value; Staging; System; Testing; Time; Tissues; Zebrafish; base; bone; cartilage development; cell behavior; craniofacial; design; gain of function; in vivo; insight; mutant; novel; programs; reconstitution; research study; response; skeletal; zebrafish development

DESCRIPTION (provided by applicant): How does the facial skeleton acquire its characteristic shape? What is the developmental basis of craniofacial birth defects in humans? The long-term goal of this proposal is to understand how epithelia communicate with skeletal precursors to generate precise cellular arrangements of cartilage and bone in the face. Zebrafish is an excellent system to model vertebrate development. This proposal uses strengths of the zebrafish system - powerful forward genetics, the ability to manipulate embryos, and in vivo imaging - to understand the tissue interactions, molecular signalling, and cell biology that specify cartilage shape. Development of the facial skeleton involves an interplay between intrinsic factors that give skeletal precursors a set identity and extrinsic signals from neighboring epithelia. The first aim is to examine how skeletal precursors acquire dorsal identity, and then how this dorsal identity allows them to respond to specific signals from neighboring epithelia. In a newly identified pucker mutant, the dorsal skeleton is transformed to a ventral character, and the expression of ventral dlx genes is expanded dorsally. The cloning and characterization of pucker will provide insights into how the dorsal skeleton is specified and shaped. In the second aim, the identity of the endodermal signals that act on skeletal precursors is investigated. Avian experiments demonstrate a role for endoderm in skeletal patterning, yet it is unclear whether the endoderm signals directly to skeletal precursors at pharyngeal arch stages. Ablation and graft experiments will test that the endoderm directly patterns facial cartilage at arch stages, and gain-of-function studies will test that the endoderm patterns cartilage by secreting distinct combinations of Fgfs and Hhs. In the third aim, the cell biology of epithelial-mesenchymal interactions in the face is investigated. Time-lapse imaging will test the model that endodermal epithelia initiate morphology and polarity changes in preskeletal mesenchyme that lead to the formation of cell condensations, a poorly understood developmental intermediate. The role of the endoderm in later cell rearrangements that refine cartilage shape will also be examined. The completion of these aims will further our understanding of facial skeleton development and lead to the better diagnosis, prevention, and treatment of human craniofacial disorders. In addition, the basic developmental knowledge obtained will be essential for the design of cell-based therapies aimed at regenerating the facial skeleton.

描述（申请人提供）：面部骨骼如何获得其特征形状？人类颅面部出生缺陷的发育基础是什么？该提案的长期目标是了解上皮细胞如何与骨骼前体进行通信，以生成面部软骨和骨骼的精确细胞排列。斑马鱼是模拟脊椎动物发育的优秀系统。该提案利用斑马鱼系统的优势——强大的正向遗传学、操纵胚胎的能力和体内成像——来了解指定软骨形状的组织相互作用、分子信号传导和细胞生物学。面部骨骼的发育涉及赋予骨骼前体一定身份的内在因素和来自邻近上皮细胞的外在信号之间的相互作用。第一个目标是研究骨骼前体如何获得背侧特征，以及这种背侧特征如何使它们能够对来自邻近上皮细胞的特定信号做出反应。在新发现的皱褶突变体中，背侧骨骼转变为腹侧特征，腹侧 dlx 基因的表达在背侧扩展。褶皱的克隆和表征将有助于深入了解背部骨骼的具体和形状。第二个目标是研究作用于骨骼前体的内胚层信号的身份。鸟类实验证明了内胚层在骨骼模式形成中的作用，但尚不清楚内胚层是否在咽弓阶段直接向骨骼前体发出信号。消融和移植实验将测试内胚层在足弓阶段直接塑造面部软骨，功能获得研究将测试内胚层通过分泌 Fgfs 和 Hhs 的不同组合来塑造软骨。第三个目标是研究面部上皮间质相互作用的细胞生物学。延时成像将测试内胚层上皮引发前骨骼间充质形态和极性变化的模型，从而导致细胞凝集的形成，细胞凝集是一种知之甚少的发育中间体。还将检查内胚层在随后细化软骨形状的细胞重排中的作用。这些目标的完成将进一步加深我们对面部骨骼发育的理解，并更好地诊断、预防和治疗人类颅面疾病。此外，获得的基本发育知识对于设计旨在再生面部骨骼的细胞疗法至关重要。