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.
