The reelin signaling pathway has been identified as a critical regulator of cell positioning in the developing central nervous system. Reelin binds to the low-density lipoprotein receptors ApoER2 and VLDLR that are expressed on the surfaces of migrating cells. Reelin signaling induces phosphorylation of the intracellular adaptor protein Dab1, triggering a cascade that modulates cytoskeletal activity ultimately regulating cell migration. Reelin signaling has been implicated in the development of a number of central nervous system regions including the cortex, hippocampus, cerebellum and spinal cord. Preliminary evidence from my laboratory suggests that reelin signaling and/or members of the reelin signaling pathway may also function outside the nervous system. Using a Dab1 reporter mouse, we have identified several novel regions where reelin signaling might be utilized, including the developing mammary glands and limbs. This finding suggests that reelin signaling may modulate cell migration and positioning in multiple tissues in developing embryos. The proposed study will address the role of reelin signaling in the mammary gland. First, we will determine when and where members of the reelin signaling pathway are expressed in the developing mammary gland. Second, we will address whether reelin signaling can guide the migration and positioning of mammary epithelial cells. Third, we will determine whether reelin signaling is required for the in vivo migration of mammary gland cells. Together, these studies will explore possible roles for reelin signaling in regulating cell migration and positioning outside the nervous system. Understanding how cell positioning and migration are regulated is critical to understanding how an embryo develops, but it is also critical in understanding the biology of cancer cells. Breast cancers involve the unchecked proliferation and migration of mammary gland cells. Understanding how this migration is regulated during normal development may provide avenues for designing strategies to limit or arrest this migration in invasive breast cancers. PUBLIC HEALTH RELEVANCE: Cell migration is the process by which cells move from where they are born to where they are needed in a developing embryo. This process is critically important for normal embryonic development because most cells migrate to form and colonize tissues of the body. Like cells in developing embryos, cancer cells are highly migratory and invasive;thus, by characterizing the molecular cascades involved in regulating cell migration during normal development, we hope to identify elements that may be targeted during cancer treatment to reduce or inhibit the migration of these cells.