Signaling Hierarchies in Vertebrate Development

这个项目的长期目标是确定脊椎动物胚胎中特定命运的细胞结构域，并了解这些结构域最初是如何形成的，随后是如何细化的，以及如何逐步细分的，以便单个细胞最终能够根据它们的位置表达高度受限的命运。在目前的项目期间，已经很明显，广泛保守的细胞间信号分子在每个发育步骤中都被使用，并且信号相互作用发生在等级级联中。了解这些信号如何作用和相互作用，以及信号层次的逻辑，对于理解发育模式至关重要。即将到来的项目阶段的目标是获得对胚胎特定细胞命运和区域的理解。该目标将在三个组成项目中实现。Kimmel的项目：头骨力模式的信号；韦斯特菲尔德项目：前中枢神经系统模式的信号；艾森项目：神经元规范过程中信号通路之间的相互作用。每个项目都提出利用斑马鱼进行基于基因的发育分析。基因表达分析和涉及野生型和突变型胚胎之间细胞移植的镶嵌分析将揭示信号细胞和对信号作出反应的细胞-功能丧失和获得实验将建立不同信号之间的层次相互作用，如结节，刺猬，类维生素a，甲状腺激素和神经营养因子。所有这些信号通路的缺陷，以及其他将被研究的缺陷，都与特定的人类疾病有关；因此，这项研究的结果将直接关系到人类的健康。五个核心设施，包括一个独特的遗传学/斑马鱼设施，将为这些组成项目提供支持。

The long term goals of this Program Project are to define the domains of cells specified to particular fates in a vertebrate embryo, and to learn how these domains are initially patterned, subsequently refined, and progressively subdivided such that individual cells can finally express highly restricted fates according to their positions. During the current project period it has become apparent that widely conserved intercellular signaling molecules are used at each of the developmental steps, and that the signaling interactions occur in hierarchical cascades. Understanding how these signals act and interact, and the logic of the signaling hierarchy, is critical for understanding developmental patterning. The goal for the coming project period is to obtain this understanding for particular cell fates and regions of the embryo. The goal will be achieved in three Component Projects. Project by Kimmel: Signals that pattern the skull forces; Project by Westerfield: Signals that pattern the anterior central nervous system; Project by Eisen: Interactions among signaling pathways during neuronal specification. Each project proposes a genetically based developmental analysis using zebrafish. Gene expression analysis, and mosaic analyses involving transplantation of cells between wild-type and mutant embryos, will reveal the signaling cells and cells that respond to the signals Loss- and gain-of function experiments will establish hierarchical interactions among signals as diverse as nodals, hedgehogs, retinoids, thyroid hormones, and neurotropic factors. Defects in all these signaling pathways, as well as others that will be examined, are implicated in particular human diseases; hence, results from this research will have direct bearing on human health. Five Core Facilities, including a unique Genetics/Zebrafish Facility, will provide support for these Component Projects.