Role of F-BAR proteins in neuronal development

描述（由申请人提供）：膜突起和内陷都是基本的细胞过程，因此受到严格调控。重要的是，这些明显的拮抗过程控制质膜的大小和分子组成，是细胞迁移所必需的，并需要肌动蛋白聚合。然而，关于细胞膜突出和内陷如何整合到细胞功能中，特别是在神经系统中，却很少有数据。F-BAR蛋白是通过其F-BAR结构域参与膜曲率传感和变形的蛋白质超家族，使它们在这两个过程中成为潜在的重要参与者。在结构上，它们形成弯曲的二聚体，其在内吞囊泡周围自我多聚化，导致其伸长成小管。CIP 4蛋白家族（TOCA 1、FBP 17和CIP 4）是F-BAR蛋白的一个家族，也结合肌动蛋白相关蛋白。与其他F-BAR蛋白一样，CIP 4家族被认为主要在膜内陷和内吞中起作用，但我们最近的工作也涉及CIP 4在神经元膜突起中的作用。我们最近发现，CIP 4转染诱导肌动蛋白为基础的肋骨和面纱周围的皮层神经元。这些肋和面纱分别类似于丝状伪足和片状伪足，并导致扇贝状片状伪足，充满了由富含肌动蛋白的膜面纱连接的薄肌动蛋白束。在原代皮层神经元中，CIP 4家族蛋白与肋骨和面纱的突出边缘特异性相关，将它们定位在膜变形和肌动蛋白聚合的联系处。在该提议中，我们将测试以下新的假设：1）CIP 4家族的F-BAR蛋白通过与蛋白质的不同子集相互作用而在神经元和非神经元细胞中以背景特异性方式起作用，以及2）CIP 4通过在迁移期间抑制轴突/树突生长而在神经元中起作用。这项工作将为蛋白质如何在不同细胞类型中发挥特定功能以及神经元如何在迁移和轴突形成过程中协调膜突起和内陷提供基本见解。CIP 4与亨廷顿病和几种癌症有关，这强调了了解这个蛋白质家族如何在不同细胞类型中以特定方式发挥作用的重要性。

DESCRIPTION (provided by applicant): Both membrane protrusion and invagination are fundamental cellular processes and are therefore tightly regulated. Importantly, these apparently antagonistic processes control the size and molecular composition of the plasma membrane, are essential for cellular migration and require actin polymerization. However, there is little dat on how membrane protrusion and invagination are integrated in cellular function, especially in the nervous system. F-BAR proteins are a superfamily of proteins involved in membrane curvature sensing and deformation through their F-BAR domain, positioning them as potentially important players in both of these processes. Structurally, they form a curved dimer that self-multimerizes around endocytic vesicles, causing their elongation into tubules. The CIP4 family of proteins (TOCA1, FBP17 and CIP4) is one family of F-BAR proteins that also bind actin-associated proteins. Like other F-BAR proteins, the CIP4 family is thought to function primarily in membrane invagination and endocytosis, but our recent work has implicated CIP4 in neuronal membrane protrusion as well. We have recently discovered that CIP4 transfection induces actin-based ribs and veils around the periphery of cortical neurons. These ribs and veils are similar to filopodia and lamellipodia, respectively, and result in an scalloped lamellipodia, fille with thin actin bundles connected by actin-rich veils of membrane. In primary cortical neurons CIP4 family proteins are specifically associated with the protruding edges of ribs and veils, positioning them at the nexus of membrane deformation and actin polymerization. In this proposal we will test the following novel hypotheses: 1) F-BAR proteins of the CIP4 family act in a context- specific manner in neurons and non-neuronal cells by interacting with a distinct subset of proteins and 2) CIP4 functions in neurons by inhibiting axon/dendrite outgrowth during migration. This work will provide fundamental insights into how proteins may serve context-specific functions in different cell types and how neurons coordinate membrane protrusion and invagination during migration and axon formation. CIP4 has been implicated in Huntington's disease and several forms of cancer, underscoring the importance of understanding how this family of proteins may function in a context-specific fashion in different cell types.