Biological Roles of Nodal Related Genes in Embryogenesis

描述（由申请人提供）：多细胞 脊椎动物的胚胎是严重依赖于细胞间通讯。在 在这个过程中，一个普遍的机制是蛋白质信号的分泌， 与其他细胞上的特定膜受体结合，启动信号 转导，影响核基因活性，并改变细胞命运。这里我们 专注于Nodal（青蛙中的Xnr）信号，它在所有脊椎动物的胚胎中 到目前为止研究-鱼，青蛙，小鸡，哺乳动物（包括人类）-是至关重要的， 胚层诱导和图案化，以及左右不对称 内脏器官和心血管的形态发生和定型 系统有效诱导信号的产生和作用必须精确地 在空间和时间上进行调节，以产生正确的数量和类型， 胚胎组织一个积极的节点自动调节回路，和一个反馈回路 涉及由Nodal信号传导诱导的Nodal抑制剂Lefty/antivin， 已被定义。我们假设这些相互依赖的循环提供了 节基因的持续时间和空间范围的灵活调节 在胚胎组织中的表达和功能。我们将分析这些循环 从功能和机制上利用青蛙的实验属性， 胚胎我们将：（1）确定“左右信号”是如何产生的， 传播，并在胚胎中发挥作用。(2)确定Xatv如何调节 在中胚层诱导和L-R特化期间的节介导的诱导。（三） 描述Xatv的处理过程，并确定差分处理是否 Xatv前蛋白的活性影响其对Xnr配体的作用。这些研究集中在 在一个基本的诱导途径调节细胞命运的规范和协调 形态发生和人类的先天性缺陷。在细胞生物学水平上， 他们解决了一个信号如何影响细胞命运的基本问题， 原肠胚形成，但后来的行为，以调节形态发生行为的公开 等同的细胞类型。

DESCRIPTION (provided by applicant): The development of the multicellular vertebrate embryo is critically dependent upon intercellular communication. In this process, a widespread mechanism is the secretion of protein signals that bind to specific membrane receptors on other cells, initiate signal transduction, affect nuclear gene activity, and alter cell fate(s). Here, we focus on signaling by Nodal (Xnr in frogs), which in embryos of all vertebrates so far studied - fish, frog, chick, mammal (including humans)- is critical for germ layer induction and patterning, and the left-right asymmetric morphogenesis and stereotyped shaping of the internal organs and cardiovascular system. The production and action of potent inducing signals must be precisely regulated, spatially and temporally, to produce the right amounts and types of embryonic tissue. A positive Nodal auto-regulatory loop, and a feedback loop involving a Nodal inhibitor Lefty/antivin that is induced by Nodal signaling, have been defined. We hypothesize that these interdependent loops provide for flexible regulation of the duration and spatial extent of nodal gene(s) expression and function in embryonic tissues. We will analyze these loops functionally and mechanistically using the experimental attributes of the frog embryo. We will: (1) Determine how "Left-Right signals" are generated, transmitted, and act in the embryo. (2) Determine how Xatv modulates Nodal-mediated induction during mesoderm induction and L-R specification. (3) Characterize the processing of Xatv, and determine if differential processing of the Xatv proprotein affects its action on Xnr ligands. These studies focus on a basic inductive pathway regulating cell fate specification and coordinated morphogenesis, and to congenital defects in humans. At a cell biological level, they address the fundamental issue of how one signal affects cell fates during gastrulation, but later acts to regulate the morphogenetic behavior of overtly equivalent cell types.