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ApoER 2和VLDLR结合。Reelin信号传导诱导细胞内衔接蛋白Dab 1的磷酸化，触发调节细胞骨架活性的级联反应，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，包括皮质、海马、小脑和脊髓。我实验室的初步证据表明，reelin信号和/或reelin信号通路的成员也可能在神经系统外发挥作用。使用Dab 1报告小鼠，我们已经确定了几个新的区域，其中reelin信号可能被利用，包括发育中的乳腺和四肢。这一发现表明，reelin信号可能调节细胞迁移和定位在多个组织中发育胚胎。拟议的研究将解决的作用，reelin信号在乳腺。首先，我们将确定何时何地reelin信号通路的成员在发育中的乳腺表达。其次，我们将讨论是否reelin信号可以引导乳腺上皮细胞的迁移和定位。第三，我们将确定是否reelin信号是必需的乳腺细胞在体内迁移。总之，这些研究将探索reelin信号在调节细胞迁移和定位神经系统外的可能作用。了解细胞定位和迁移是如何调节的，对于了解胚胎如何发育至关重要，但对于了解癌细胞的生物学也至关重要。乳腺癌涉及乳腺细胞的不受抑制的增殖和迁移。了解这种迁移在正常发育过程中是如何调节的，可能会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。 公共卫生相关性：细胞迁移是细胞从出生地移动到发育胚胎所需位置的过程。这个过程对于正常的胚胎发育至关重要，因为大多数细胞迁移形成并定居在身体的组织中。与发育中的胚胎中的细胞一样，癌细胞具有高度迁移性和侵袭性;因此，通过表征正常发育期间参与调节细胞迁移的分子级联，我们希望确定在癌症治疗期间可能靶向的元素，以减少或抑制这些细胞的迁移。

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.