Signaling Hierarchies in Vertebrate Development

描述(由申请人提供)：为了让所有儿童都有机会充分发挥其健康生活的潜力，远离疾病，了解发育模式背后的机制以及这种模式如何在人类疾病中出错是至关重要的。该项目的目标是阐明一种这样的机制--细胞间相互信号的功能，该信号指定胚胎细胞穿越特定的发育途径并表达受限的命运。这一目标将在三个组成部分的项目中为三组细胞命运实现，使用斑马鱼，这是俄勒冈大学这个小组开创的一种广泛使用的动物模型生物。这些项目利用斑马鱼的属性进行发育遗传分析，包括基因表达研究、遗传镶嵌研究，以及将确定相互作用性质的功能丧失和功能获得实验。这些项目包括筛选新的突变和在这些信号通路中重要的基因，由独特的斑马鱼设施促进，斑马鱼设施是四项核心服务之一。项目一“骨骼形成中的相互信号”测试了有关信号分子在塑造腭部骨骼形状和软骨骨发育途径中的功能的假说。研究结果将加深对颅骨上皮细胞与间充质细胞、软骨细胞与骨祖细胞之间信号通路的理解。因此，它们将帮助我们了解腭裂，这是人类最常见的出生缺陷之一，以及将在未来十年影响近五分之一美国人的骨性关节炎。项目II“突触发生中的相互信号”测试了一个新的假设，即Usher基因编码的蛋白质在一个复合体中相互作用，在感觉细胞和神经元之间调节相互信号，感觉细胞与该复合体形成突触连接。这些分析将确定Usher基因网络的关键组成部分，并提供对Usher综合征的完整了解，Usher综合征是导致耳聋和失明的最常见原因。项目III，“胃肠道发育中的相互信号”，探索了肠道微生物区系通过调节高度保守的分子信号Notch来影响肠道上皮和肠道神经系统细胞命运决定的假设。这项工作将阐明相互信号及其在炎症性肠病和相关疾病等疾病中是如何出错的，这些疾病加起来影响了超过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.