Role of F-BAR proteins in neuronal development

描述(申请人提供)：膜突起和内陷都是基本的细胞过程，因此受到严格的调控。重要的是，这些明显的拮抗过程控制着质膜的大小和分子组成，是细胞迁移所必需的，需要肌动蛋白聚合。然而，关于膜突起和内陷如何在细胞功能中整合的数据很少，特别是在神经系统中。F-bar蛋白是一个超家族蛋白，通过其F-bar结构域参与膜曲率感知和变形，在这两个过程中都有潜在的重要作用。在结构上，它们形成一个弯曲的二聚体，在内吞囊泡周围自我聚合，导致它们伸长成小管。CIP4蛋白家族(TOCA1、FBP17和CIP4)是F-bar蛋白家族中的一员，它还与肌动蛋白相关蛋白结合。像其他F-bar蛋白一样，CIP4家族被认为主要在膜内陷和内吞中发挥作用，但我们最近的工作也表明CIP4与神经细胞膜突起有关。我们最近发现，CIP4的转染诱导了皮质神经元周围以肌动蛋白为基础的肋骨和面纱。这些肋骨和面纱分别类似于丝状足和片状脂膜，并导致扇形片状脂膜，由富含肌动蛋白的膜面纱连接着细小的肌动蛋白束。在初级皮质神经元中，CIP4家族蛋白特定地与肋骨和面纱的突出边缘相关，将它们定位在膜变形和肌动蛋白聚合的连接处。在这个提议中，我们将检验以下新的假设：1)CIP4家族的F-bar蛋白通过与不同的蛋白质亚集相互作用在神经元和非神经元细胞中以上下文特有的方式发挥作用；2)CIP4通过抑制迁移过程中轴突/树突的生长在神经元中发挥作用。这项工作将为蛋白质如何在不同类型的细胞中发挥上下文特定的功能，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的见解。CIP4与亨廷顿氏病和几种形式的癌症有关，这突显了了解这一蛋白家族如何在不同细胞类型中以特定于上下文的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.