Molecular Roles of Syndecans in Development

描述(申请人提供)：在所有脊椎动物的早期胚胎发育过程中，两侧对称性被破坏，形成胚胎的左右轴。LR信息被传递到包括心脏在内的各种发育中的器官原基。尽管我们对控制LR发育中间步骤的一系列复杂途径的理解已经取得了重大进展，但负责LR轴启动的基因、分子和细胞机制尚不清楚。 Syndecan-2是一种单程跨膜的硫酸乙酰肝素蛋白多糖。我们最近发现，LR发育的最早步骤之一是通过依赖蛋白激酶C伽马(PKCGamma)的Syndecan-2不对称磷酸化来介导的。这启动了一条新的“内向外”信号通路，在原肠胚形成的早期，不对称磷酸化的Syndecan-2将LR信息从外胚层细胞转导到迁移的中胚层细胞。这项研究将阐明Syndecan功能中引发LR不对称的分子途径，以及Syndecan-2向迁移细胞发送至少两个不同信号(左或右)的机制。除了LR的发展，这项拟议的研究还将阐明syndecan-2的另外两个作用：它通过与Pinch和整合素形成一个信号复合体来调节纤维连接蛋白的纤维形成，以及它能够重新定位迁移中胚层细胞的方向。 这项研究的长期目标是显著增加我们对控制心血管发育、细胞-细胞信号、细胞外基质形成和细胞迁移的基因和机制的了解。这项研究得出的原理将适用于发育和疾病中广泛的细胞-细胞信号事件。

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.