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《调查者摘要》)：头面部缺陷 这是由于控制头部发育的正常机制被破坏所致。 因此，了解遗传性头面部疾病的基础需要 关于指导模式的胚胎分子和遗传过程的知识 在头部形成队形。其中包括组织间的相互作用 骨源性间充质及其向软骨的凝聚和分化 和骨骼，以及它们之间的相互连接，形成一个功能强大的骨骼网络。 这项建议使用遗传学和胚胎学来研究这些问题。 斑马鱼作为模型的优势。斑马鱼的胚胎形成了一个简单的， 分段组织的咽部骨骼，其中与人类骨骼同源 元素是可识别的，许多形成这些片段的基因 一直保存在鱼和人类之间。据认为，一名少校 每个咽段内的图案成分是内皮素-1(ET-1)， 引导软骨生成和成骨的模式的信号。实验 建议使用一组斑马鱼来剖析这种信号的作用 突变体包括ET-1本身的一个突变体以及突变体和拮抗剂 ET受体。目标1是表征Ephin和Eph受体的基因 酪氨酸激酶家族在控制神经波峰中的作用 形态发生及其对ET-1的响应。目标2是分析一个突变体 称为Schmerle，其表型类似于ET-1功能丧失，在更多 并克隆其潜在的遗传基础。目标3侧重于定义 咽部或咽部之间哪些特定的组织相互作用需要ET-1 上皮或中胚层和骨骼发育的神经脊 移植ET-1突变体对骨骼生化基础的研究 图案化。