Signaling Hierarchies in Vertebrate Development

描述（由申请人提供）：为了使所有儿童都有机会在没有疾病的情况下实现其健康生活的全部潜力，了解发育模式的潜在机制以及这种模式如何在人类疾病中出错是至关重要的。本项目的目标是阐明一种这样的机制，即指定胚胎细胞穿越特定发育途径并表达受限制命运的相互细胞间信号传导的功能。这一目标将在三个组成部分的项目中实现三组细胞命运，使用斑马鱼，一种被广泛使用的动物模型生物，由俄勒冈大学的这个小组首创。这些项目利用斑马鱼的特性进行发育遗传分析，包括基因表达研究、基因镶嵌调查和功能丧失和获得实验，这些实验将建立相互作用的本质。这些项目包括筛选在这些信号通路中重要的新突变和基因，由独特的斑马鱼设施（四个核心服务之一）提供支持。项目一，“骨骼形成中的相互信号传导”，测试了关于信号分子在腭骨骼形状和软骨骨发育途径中功能的假设。研究结果将有助于进一步了解颅上皮细胞和间质之间以及软骨和骨祖细胞之间的信号通路。因此，他们将告诉我们对腭裂的理解，腭裂是人类最常见的先天缺陷之一，而骨关节炎将在未来十年影响近五分之一的美国人。项目二，“突触发生中的互惠信号传导”，测试了一个新的假设，即Usher基因编码的蛋白质在感觉细胞和神经元之间的复杂介导互惠信号传导中相互作用，感觉细胞与神经元形成突触连接。这些分析将确定Usher基因网络的关键组成部分，并提供对Usher综合征的综合理解，这是耳聋和失明的最常见原因。项目三，“胃肠道发育中的相互信号传导”，探讨肠道微生物群通过调节高度保守的分子信号Notch来影响肠道上皮细胞和肠神经系统细胞命运决定的假设。这项工作将阐明相互信号，以及它如何在炎症性肠病和相关疾病等疾病中出错，这些疾病总共影响了超过10%的美国人口。

DESCRIPTION (provided by applicant): For all children to have the opportunity to achieve their full potential for healthy lives, free from disease, it is essential to understand mechanisms underlying developmental patterning and how this patterning can go awry in human disease. The goal of this program project is to elucidate one such mechanism - the function of reciprocal intercellular signaling that specifies embryonic cells to traverse particular developmental pathways and express restricted fates. This goal will be achieved for three sets of cell fates in three component projects, using the zebrafish, a widely-utilized animal model organism pioneered by this group at the University of Oregon. The projects take advantage of the attributes of the zebrafish for developmental genetic analyses, including gene expression studies, genetic mosaic investigations, and loss- and gain-of-function experiments that will establish the nature of the interactions. The projects include screens for new mutations and genes important in these signaling pathways, facilitated by the unique Zebrafish Facility, one of four core services. Project I, "Reciprocal signaling in skeletogenesis", tests hypotheses about the functioning of signaling molecules in patterning the shape of the palatal skeleton and the pathway of chondral bone development. Results will improve understanding of signaling pathways between cranial epithelia and mesenchyme, and between cartilage and bone progenitors. They will thereby inform our understanding of cleft palate, one of the most common human birth defects, and osteoarthritis that will affect nearly one in five Americans during the coming decade. Project II, "Reciprocal signaling in synaptogenesis", tests a novel hypothesis that Usher genes encode proteins that interact in a complex mediating reciprocal signaling between sensory cells and neurons with which the sensory cells form synaptic connections. The analyses will identify the critical components of the Usher gene network and provide an integrated understanding of Usher syndrome, the most frequent cause of deafness and blindness. Project III, "Reciprocal signaling in gastrointestinal tract development", explores the hypothesis that gut microbiota influence cell fate decisions in gut epithelium and enteric nervous system by modulating a highly conserved molecular signal, Notch. The work will elucidate reciprocal signaling and how it goes awry in disorders such as inflammatory bowel disease and related disorders that together affect more than 10% of the U.S. population.