Funktionen des zellulären Prion Proteins für die Entwicklung von Zell-Zell Kontakten und Axonwachstum

GPI锚定的Prion蛋白(PrP)是众所周知的，因为它的错误折叠构象是人和动物神经退行性疾病(如BSE)的病原体--但人们对它的生理功能知之甚少。我们在斑马鱼和细胞上的研究表明PrP在细胞间的通信/黏附以及与钙粘附素黏附系统的相互作用中发挥作用。此外，我们的结果显示PrP与微域支架蛋白Reggie(Flotillin)及其信号伙伴相关的信号转导。基于这些发现，我们提出了一个假设，即在Reggie微域中聚集允许PrP将信号转导到细胞内，并与肌动蛋白细胞骨架进行通信。在这里，我们旨在了解PrP与Reggie及其同系物一起在细胞-细胞接触形成中的贡献，以及对钙粘附素的招募以形成联系。这两个事件都需要肌动蛋白细胞骨架的重组。因此，我们将分析特定的接头和信号转导分子，如CAP、afadin、src酪氨酸激酶、p120ctn、Rho-GTP酶等在细胞接触形成、肌动蛋白细胞骨架调控和轴突生长中的作用。我们的分析将包括丝状伪足和片状伪足中PrP-Reggie功能的测定，它们建立了细胞之间的第一次接触，并可能招募p120和钙粘附素来促进细胞接触成熟。

The GPI-anchored Prion protein (PrP) is well-known since its misfolded conformer is the causative agent of the neurodegenerative diseases in man and animals (such as BSE) - but its physiological function is poorly understood. Our work in zebrafish and cells suggests a role of PrP in cell-cell communication/adhesion and interaction with the cadherin adhesion system. Our results, moreover, show signal transduction by PrP in association with the microdomain scaffolding protein reggie (flotillin) and its signalling partners. Based on these findings we developed the hypothesis that clustering in reggie microdomains allows PrP to transduce signals into the cell and to communicate with the actin cytoskeleton. Here, we aim at understanding the contribution of PrP to cell-cell contact formation in conjunction with reggie and its associates and to the recruitment of cadherins to forming contacts. Both events require actin cytoskeletal reorganisation. We will therefore analyse the contribution of specific adapter and signal transduction molecules such as CAP, afadin, src tyrosine kinases, p120ctn, Rho-GTPases etc. to cell contact formation, regulation of the actin cytoskeleton and neurite growth. Our analysis will include determination of PrP-reggie function in filopodia and lamellipodia which establish first contacts between cells and which may recruit p120 and cadherins for cell contact maturation.