Epithelial-mesenchymal interactions in facial patterning

面部图案中的上皮-间质相互作用

• 批准号: 7935557
• 负责人: Gage D Crump
• 金额: $ 8.12万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-03-08 至 2011-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7935557
• 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（由申请人提供）：面部骨骼是如何获得其特征形状的？人类颅面出生缺陷的发育基础是什么？这项计划的长期目标是了解上皮细胞如何与骨骼前体细胞沟通，以产生面部软骨和骨骼的精确细胞排列。斑马鱼是一个很好的脊椎动物发育模型。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-来了解组织相互作用，分子信号和指定软骨形状的细胞生物学。面部骨骼的发育涉及给予骨骼前体一套身份的内在因素和来自邻近上皮的外在信号之间的相互作用。第一个目的是研究骨骼前体如何获得背侧身份，然后这种背侧身份如何使他们能够响应来自邻近上皮细胞的特定信号。在一个新发现的皱褶突变体中，背侧骨骼转化为腹侧特征，腹侧dlx基因的表达向背侧扩展。pucker的克隆和特征化将为了解背侧骨骼是如何指定和成形的提供见解。在第二个目标中，研究作用于骨骼前体的内胚层信号的身份。鸟类实验表明内胚层在骨骼模式中的作用，但目前还不清楚内胚层是否直接向咽弓阶段的骨骼前体发出信号。消融和移植实验将测试内胚层在足弓阶段直接形成面部软骨，并且功能获得研究将测试内胚层通过分泌Fgfs和Hhs的不同组合形成软骨。在第三个目标中，研究了面部上皮-间充质相互作用的细胞生物学。延时成像将测试模型，内胚层上皮细胞启动形态和极性的变化，导致形成细胞凝聚，一个知之甚少的发展中间。内胚层的作用，在以后的细胞重排，完善软骨形状也将被检查。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，并导致更好地诊断，预防和治疗人类颅面疾病。此外，所获得的基本发育知识对于设计旨在再生面部骨骼的基于细胞的疗法至关重要。