Role of F-BAR proteins in neuronal development

F-BAR 蛋白在神经元发育中的作用

• 批准号: 9039494
• 负责人: Erik W Dent
• 金额: $ 32.21万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-05-15 至 2018-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9039494
• 关键词: Actins; Address; Adult; Affect; Amino Acids; Axon; Binding; Brain; Cell membrane; Cell physiology; Cells; Cerebellum; Chimeric Proteins; Clathrin; Data; Dendrites; Development; Dynamin; Endocytic Vesicle; Endocytosis; Excision; Family; Family member; Filopodia; Fluorescence Microscopy; Gap Junctions; Health; Hippocampus (Brain); Huntington Disease; Image; Immigration; Individual; Life; Link; Malignant Neoplasms; Mammalian Cell; Membrane; Molecular; Nervous system structure; Neuroglia; Neurons; Pattern; Pharmacological Treatment; Positioning Attribute; Process; Protein Family; Proteins; RNA Interference; Radial; Research; Role; Scallop; Slice; TRIP10 gene; Tertiary Protein Structure; Testing; Total Internal Reflection Fluorescent; Transfection; Transferrin; Wild Type Mouse; Work; base; cell motility; cell type; dimer; human disease; immunocytochemistry; insight; knock-down; microscopic imaging; migration; molecular size; neuron development; novel; overexpression; polymerization; research study; rib bone structure; uptake

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.

描述（由申请人提供）：膜的突出和起伏都是基本的细胞过程，因此受到严格调节。重要的是，这些显然是拮抗过程控制质膜的大小和分子组成，对于细胞迁移至关重要，需要肌动蛋白聚合。但是，几乎没有关于膜突起和内陷是在细胞功能中的整合，尤其是在神经系统中的情况。 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的超家族，在这两个过程中都将其定位为潜在的重要参与者。从结构上讲，它们形成弯曲的二聚体，该二聚体在内吞囊泡周围自我培养，从而导致其伸长到小管中。 CIP4蛋白的CIP4家族（TOCA1，FBP17和CIP4）是F-BAR蛋白的一个家族，也结合了肌动蛋白相关的蛋白质。像其他F-BAR蛋白一样，CIP4家族被认为主要在膜起伏和内吞作用中起作用，但是我们最近的工作也暗示了CIP4在神经元膜的突出中。我们最近发现，CIP4转染会诱导基于肌动蛋白的肋骨和面纱周围的皮质神经元周围。这些肋骨和面纱分别类似于丝状和薄片，并导致扇形的薄片，填充薄肌动蛋白束，由膜的富含肌动蛋白的面纱连接起来。在原发性皮质神经元中，CIP4家族蛋白与肋骨和面纱的突出边缘特别相关，将其定位在膜变形和肌动蛋白聚合的Nexus上。在该提案中，我们将测试以下新颖的假设：1）CIP4家族的F-BAR蛋白在神经元和非神经元细胞中以特异性方式起作用，通过与蛋白质的独特子集相互作用，而2）CIP4在迁移过程中抑制轴突/树突状产生。这项工作将提供有关蛋白质如何在不同细胞类型中发挥上下文特异性功能以及神经元如何协调膜的突出和迁移和轴突形成过程中的内脏的基本见解。 CIP4与亨廷顿氏病和几种形式的癌症有关，强调了了解这种蛋白质家庭如何以不同细胞类型的特定方式发挥作用的重要性。