Molecular Roles of Syndecans in Development

描述（由申请人提供）：在所有脊椎动物的早期胚胎发生过程中，双侧对称性被打破，从而产生胚胎左右轴。LR信息被传递到各种各样的发育器官原基，包括心脏。虽然我们已经取得了显着的进展，在LR发展的中间步骤控制一套复杂的途径的理解，基因，分子和细胞机制负责启动LR轴是未知的。 Syndecan-2是一种单通道跨膜硫酸乙酰肝素蛋白聚糖。我们最近发现，LR发展的最早步骤之一是通过蛋白激酶C γ（PKC γ）依赖的Syndecan-2的不对称磷酸化介导的。这启动了一种新的“由内而外”的信号传导途径，其中不对称磷酸化的Syndecan-2在原肠胚形成早期将LR信息从外胚层细胞转导到迁移的中胚层细胞。该提案中的研究将阐明启动多配体蛋白聚糖功能中LR不对称性的分子途径，以及多配体蛋白聚糖-2向迁移细胞发送至少两种不同信号（左或右）的机制。除了LR的发展，拟议的研究将阐明syndecan-2的另外两个作用：它通过与PINCH和整合素形成信号复合物来调节纤连蛋白原纤维形成，并且它能够重新定向迁移中胚层细胞的方向。 这项研究的长期目标是显着增加我们对控制心血管发育，细胞间信号传导，细胞外基质形成和细胞迁移的基因和机制的理解。从这项研究中得出的原则将适用于发展和疾病中广泛的细胞-细胞信号传导事件。

DESCRIPTION (provided by applicant): During early embryogenesis in all vertebrates, bilateral symmetry is broken to give rise to the embryonic Left-Right axis. LR information is transmitted to a wide variety of developing organ primordia, including the heart. Although significant advances have been made in our understanding of a complex set of pathways that control intermediate steps in LR development, the genes, molecular and cellular mechanisms responsible for the initiation of the LR axis are unknown. Syndecan-2 is a single-pass transmembrane heparan sulfate proteoglycan. We recently found that one of the earliest steps in LR development is mediated through Protein Kinase C gamma (PKCgamma)-dependent asymmetric phosphorylation of Syndecan-2. This initiates a novel "inside-out" signaling pathway, in which asymmetrically phosphorylated Syndecan-2 transduces LR information from ectoderm cells to migrating mesoderm cells during early gastrulation. The research in this proposal will elucidate the molecular pathways that initiate LR asymmetry in syndecan function and the mechanisms by which syndecan-2 can send at least two distinct signals (left or right) to migratory cells. Besides LR development, the proposed research will elucidate two other roles for syndecan-2: it regulates fibronectin fibrillogenesis, by forming a signaling complex with PINCH and integrin, and it is capable of re-orienting the direction of migrating mesoderm cells. The long-term goal of this research is to significantly increase our understanding of the genes and mechanisms that control cardiovascular development, cell-cell signaling, extracellular matrix formation, and cell migration. The principles derived from this research will be applicable to a wide range of cell-cell signaling events in development and disease.