CELL POLARITY SIGNALING IN C ELEGANS EMBRYOS

秀丽隐杆线虫的初始前后（a-p）极性是在受精时建立的。在此过程中，细胞命运的决定因素在前细胞和后细胞中发生了不同的定位。随着发育的进行，Wnt信号mom2的作用是维持和传播共同的a-p细胞极性。此外，细胞从apr-1（一种与人类大肠腺瘤性息肉病基因（APC）相关的基因）接收平行但遗传上不同的极性输入。这些途径有几个共同的成分，包括WRM-1 （β -连环蛋白相关基因）、lit1（丝氨酸/苏氨酸激酶）和POP-1 （hmg结构域转录因子）。该研究的长期目标是了解这些因素之间的遗传和分子关系，从而了解它们在秀丽隐杆线虫胚胎中控制细胞极性的作用。拟议的研究将包括WRM-1、lit1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在极性信号响应中下调POP-1活性的机制上。酵母双杂交筛选、反向遗传筛选和常规正向遗传筛选将确定与WRM-1和lit1一起起作用的其他相互作用因子。进一步的遗传和反向遗传筛选将确定参与这些途径的新因素。细胞极性的适当控制对人体组织的发育和稳态至关重要，而这一过程中的缺陷与许多形式的癌症有关。这项工作的意义在于它提供了在一个相对简单和特征良好的遗传模型系统中研究细胞极性的重要调节因子的机会。

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.