Elucidating the Molecular Mechanisms of gamma-Protocadherin Localization, Adhesion, and Biochemical Signaling: Implications for Synaptogenesis

γ-原钙粘蛋白基因簇（Pcdh-γ's）编码的22种蛋白质属于钙粘蛋白蛋白超家族，这是一大类细胞粘附分子。在小鼠中，整个Pcdh-γ基因位点的缺失导致大量神经元缺陷和出生后数小时内的动物死亡。尽管这些蛋白质对CNS发育具有明显的重要作用，但它们在细胞和生化水平上的作用模式仍然知之甚少。基本问题，如--Pcdh-γ介导细胞粘附还是它们作为细胞受体？Pcdh-γ如何整合到细胞蛋白质相互作用网络中？哪些蛋白基序负责单个Pcdh-γ在细胞中的特异性定位和运输？Pcdh-γ的多样性对其功能有多重要？- 仍然没有答复。我所提出的项目旨在回答这些问题。这些项目包括鉴定所选Pcdh-γ的相互作用伴侣，表征Pcdh-γ的拟议粘附特性及其在细胞内的定位，以及阐明Pcdh-γ同种型的翻译后修饰（如酪氨酸磷酸化）的作用。总之，这些项目有望首次全面了解Pcdh- γ控制CNS发育中重要过程的机制，如突触形成和神经元存活。

The 22 proteins encoded by the γ-Protocadherin gene cluster (Pcdh-γ’s) belong to the cadherin protein superfamily, a large group of cell adhesion molecules. Deletion of the entire Pcdh-γ gene locus in mice leads to massive neuronal defects and death of animals within hours after birth. Despite an obviously important role for these proteins for CNS development, their mode of action at the cellular and biochemical levels is still poorly understood. Essential questions such as -- Do Pcdh-γ’s mediate cell adhesion or do they rather act as cellular receptors? How are Pcdh-γ’s integrated into the cellular protein interaction network? Which protein motifs are responsible for specific localization and trafficking of individual Pcdh-γ’s in cells? How important is the diversity of Pcdh-γ’s for their function(s)? -- remain unanswered. My proposed projects aim to answer these questions. These projects include identification of the interaction partners of selected Pcdh-γ’s, characterization of the proposed adhesive properties of Pcdh-γ’s and their localization within cells, and as elucidation of the role of posttranslational modifications, such as tyrosine phosphorylation, of Pcdh-γ isoforms. Together, these projects promise to provide the first comprehensive understanding of the mechanisms by which the Pcdh- γ’s control important processes in CNS development such as synapse formation and neuronal survival.