Signaling Hierarchies in Vertebrate Development

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，必须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。本项目的目标是阐明一种这样的机制-指定胚胎细胞穿越特定发育过程的相互细胞间信号的功能

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 (CPs), 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 analyses, genetic mosaic analyses, 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 five Core Facilities. CP 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. CP 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 deaf blindness. CP 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 US population.