Role of Endothelins in Skeletal Patterning in Zebrafish

描述（改编自研究者摘要）：颅面缺损 是由于控制头部发育的正常机制受到破坏而引起的。 因此，了解遗传性颅面疾病的基础需要 胚胎分子和遗传过程的知识，指导模式 头部形成。这些包括组织相互作用， 成骨间充质，其浓缩和分化成软骨 和骨骼，以及它们之间的相互连接，形成一个功能性的骨骼网络。 这项建议利用遗传学和胚胎学的方法来研究这些问题。 以斑马鱼为模型的优势。斑马鱼胚胎形成一个简单的， 分节组织的咽部骨骼，其中与人类骨骼同源 基因片段是可识别的， 在鱼类和人类之间是保守的。据认为， 每个咽段内的图案化组分是内皮素-1（Et-1）， 一种指导软骨形成和骨形成模式的信号。实验 提出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 的Et受体。目的1是鉴定ephrin和eph受体的基因 酪氨酸激酶家族与神经嵴的控制有关 形态发生及其对Et-1的反应。目的2是分析一个突变体 称为schmerle，其表型类似于Et-1功能的丧失， 并克隆其潜在的遗传基础。目标3侧重于定义 哪些特定的组织相互作用需要Et-1， 上皮或中胚层和成骨神经嵴， Et-1突变体的移植，以剖析骨骼肌的生化基础， 模式化

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.