Reelin signaling and mammary gland development

描述（由申请人提供）：reelin信号通路已被确定为发育中的中枢神经系统中细胞定位的关键调节因子。Reelin与迁移细胞表面表达的低密度脂蛋白受体ApoER2和VLDLR结合。Reelin信号传导诱导细胞内接头蛋白Dab1的磷酸化，触发级联调节细胞骨架活性，最终调节细胞迁移。Reelin信号传导与许多中枢神经系统区域的发育有关，包括皮层、海马、小脑和脊髓。我实验室的初步证据表明，reelin信号传导和/或reelin信号传导途径的成员也可能在神经系统之外发挥作用。使用Dab1报告小鼠，我们已经确定了几个可能利用reelin信号的新区域，包括发育中的乳腺和四肢。这一发现表明，reelin信号传导可能调节胚胎发育过程中多种组织中的细胞迁移和定位。本研究将探讨reelin信号在乳腺中的作用。首先，我们将确定reelin信号通路成员在发育中的乳腺中的表达时间和位置。其次，我们将探讨reelin信号是否可以指导乳腺上皮细胞的迁移和定位。第三，我们将确定乳腺细胞的体内迁移是否需要reelin信号。总之，这些研究将探索reelin信号在调节细胞迁移和神经系统外定位中的可能作用。了解细胞的定位和迁移是如何被调控的，这对于理解胚胎的发育是至关重要的，但对于理解癌细胞的生物学也是至关重要的。乳腺癌与乳腺细胞不受控制的增殖和迁移有关。了解这种迁移在正常发育过程中是如何被调节的，可能为设计限制或阻止浸润性乳腺癌中这种迁移的策略提供途径。

DESCRIPTION (provided by applicant): 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.