CELL POLARITY SIGNALING IN C ELEGANS EMBRYOS

线虫最初的前-后(a-p)极性是在受精时建立的。随之而来的是一系列不对称的细胞分裂，在此期间，细胞命运决定因素变得不同地定位于前部和后部细胞。随着发育的进行，Wnt信号MoM-2具有维持和传播共同的a-p细胞极性的功能。此外，细胞接受来自apr-1的平行但在遗传上不同的极性输入，apr-1是与人类腺瘤性息肉病结肠基因(Apc)相关的基因。这些通路有几个共同的组成部分，包括WRM-1(β-连环蛋白相关基因)、LIT-1(丝氨酸/苏氨酸蛋白激酶)和POP-1(HMG结构域转录因子)。这项拟议研究的长期目标是了解这些因素之间的遗传和分子关系，从而了解它们在线虫胚胎细胞极性控制中的作用。拟议的研究将包括WRM-1、LIT-1和POP-1蛋白相互作用的体外和体内生化研究。这些研究将集中在WRM-1和LIT-1下调POP-1活性以响应极性信号的机制。酵母双杂交筛选、反向遗传筛选和常规正向遗传筛选将识别与WRM-1和LIT-1一起发挥作用的其他相互作用因子。进一步的遗传和反向基因筛查将确定这些途径中涉及的新因素。细胞极性的适当控制对人类组织的发育和动态平衡是必不可少的，这一过程中的缺陷与多种形式的癌症有关。这项工作的意义在于，它提供了在一个相对简单和特征明确的遗传模型系统中研究细胞极性的重要调节因素的机会。

Initial anterior-posterior (a-p) polarity in C. elegans is established at fertilization. A set of asymmetric cell divisions follow during which cell fate determinants become localized differentially in anterior and posterior cells. As development proceeds a Wnt signal, MOM-2, functions to maintain and to propagate a common a-p cellular polarity. In addition, cells receive a parallel but genetically distinct polarity input from apr-1, a gene related to the human Adenomatous polyposis coli gene (APC). These pathways share several common components including WRM-1 (a beta-catenin related gene), LIT-1 (a Ser/Thr Kinase) and POP-1 an HMG-domain transcription factor. The long-term goal of the proposed research is to understand the genetic and molecular relationships between these factors and hence to understand their role in controlling cellular polarity in the C. elegans embryo. The proposed studies will include in vitro and in vivo biochemical studies of WRM-1, LIT-1 and POP-1 protein interactions. These studies will focus on the mechanism through which WRM-1 and LIT-1 down-regulate POP-1 activity in response to polarity signaling. Yeast two hybrid screens, reverse genetic screens and conventional forward genetic screens will identify additional interacting factors that function along with WRM-1 and LIT-1. Further genetic and reverse genetic screens will identify new factors involved in these pathways. The proper control of cellular polarity is essential for the development and homeostasis of tissues in humans, and defects in this process are implicated in numerous forms of cancer. The significance of this work lies in the opportunity it provides to study important regulators of cellular polarity within a relatively simple and well characterized genetic model system.