Role of Endothelins in Skeletal Patterning in Zebrafish

内皮素在斑马鱼骨骼图案形成中的作用

• 批准号: 6719061
• 负责人: Thomas F Schilling
• 金额: $ 22.19万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-04-01 至 2006-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6719061
• 关键词: biological signal transduction; bone development; cartilage development; cell cell interaction; craniofacial; developmental genetics; embryo /fetus cell /tissue; endoderm; endothelin; ephrins; gene expression; gene mutation; genetic mapping; histogenesis; hormone receptor; hormone regulation /control mechanism; mesoderm; molecular cloning; mutant; neural crest; oral pharyngeal; osteogenesis; protein tyrosine kinase; receptor expression; tissue mosaicism; zebrafish

DESCRIPTION (Adapted from the Investigator's Abstract): Craniofacial defects result from disruptions of the normal mechanisms that control head development. Thus understanding the basis for inherited craniofacial disorders requires knowledge of the embryonic molecular and genetic processes that direct pattern formation in the head. These include the tissue interactions that establish skeletogenic mesenchyme, its condensation and differentiation into cartilages and bones, and their interconnections to form a functional skeletal network. This proposal examines these issues using the genetics and embryological advantages of zebrafish as a model. Zebrafish embryos form a simple, segmentally organized pharyngeal skeleton, where homologies with human skeletal elements are recognizable, and many of the genes that pattern these segments have been conserved between fish and humans. It is thought that a major component of patterning within each pharyngeal segment is endothelin-1 (Et-1), a signal that directs patterns of chondrogenesis and osteogenesis. Experiments are proposed to dissect the role of this signal using a set of zebrafish mutants including one mutant in Et-1 itself as well as mutants and antagonists of Et receptors. Aim 1 is to characterize genes of the ephrin and eph receptor tyrosine kinase families that we have implicated in controlling neural crest morphogenesis and their responses to Et-1. Aim 2 is to analyze one mutant called schmerle, which phenotypically resembles loss of Et-1 function, in more detail and to clone its underlying genetic basis. Aim 3 focuses on defining which specific tissue interactions require Et-1, between either the pharyngeal epithelium or mesoderm and the skeletogenic neural crest, by using cell transplantation in Et-1 mutants to dissect the biochemical basis for skeletal patterning.

描述（改编自调查员的摘要）：颅面缺陷 由控制头部发育的正常机制的破坏导致。 因此，了解继承的颅面疾病的基础需要 对导向模式的胚胎分子和遗传过程的了解 头部构成。这些包括建立的组织相互作用 骨骼生成间质，其凝结和分化为软骨 和骨骼及其互连形成功能性骨骼网络。 该建议使用遗传学和胚胎学检查了这些问题 斑马鱼作为模型的优势。斑马鱼胚胎形成一个简单的 分段组织的咽骨架，其中具有人类骨骼的同源性 元素是可识别的，许多对这些段的基因 在鱼类和人类之间保守了。认为一个专业 每个咽部段内图案的成分是内皮素-1（ET-1）， 指导软骨发生和成骨的模式的信号。实验 建议使用一组斑马鱼剖析该信号的作用 突变体在ET-1本身以及突变体和拮抗剂中包括一个突变体 ET受体。目的1是表征源自ephrin和Eph受体的基因 酪氨酸激酶家族，我们牵涉到控制神经rest的 形态发生及其对ET-1的反应。目标2是分析一个突变体 在表型上，施密勒（Schmerle 细节并克隆其基本的遗传基础。 AIM 3专注于定义 哪种特定的组织相互作用需要ET-1，两种咽之间 通过使用细胞 在ET-1突变体中移植以剖析骨骼的生化基础 图案。