F-BAR proteins in neuronal migration and process formation

破坏神经元的对称性是形成极化神经元的基本过程。神经元 发育中的大脑皮层生来就是球形细胞，它们必须延伸前导和尾随过程才能迁移 到达发育中的皮质板然后，皮质神经元延伸长轴突和树突， 这些过程来创建功能电路。皮质神经元迁移和过程延伸是关键 依赖于微管和肌动蛋白细胞骨架，但相对较少的是关于肌动蛋白细胞骨架如何 和质膜在这些事件中是协调的。膜突出和内陷是 基本的细胞活动，需要质膜和下面的肌动蛋白细胞骨架的协调。 然而，关于膜突出和内陷如何在过程中整合的数据缺乏。 生长和神经元迁移。F-BAR蛋白超家族参与膜曲率传感 和变形通过他们的F-BAR域，定位他们作为潜在的重要球员，在膜 内陷和外突。在结构上，它们形成一个弯曲的二聚体， 囊泡，导致它们伸长成小管。CIP 4蛋白家族（CIP 4、FBP 17和TOCA 1）是一组 结合肌动蛋白相关蛋白的F-BAR蛋白。与其他F-BAR蛋白一样，CIP 4家族被认为是 CIP 4主要在膜内陷和内吞中起作用，但我们最近的工作表明CIP 4在神经元细胞中起作用。 膜突起也是。CIP 4诱导的片状脂质样突起强烈抑制神经突起的生长。 文化相反，我们发现一个密切的家庭成员，FBP 17，形成内吞小管在发育中的皮质 神经元和促进突出的丝状伪足的形成，导致早熟的神经突生长。在本提案中，我们 将测试新的假设，即通过CIP 4的突出和通过FBP 17的内陷在相反的方向上起作用。 调节发育中皮层神经元迁移和突起形成的方式。具体而言，我们将： 1)确定CIP 4如何诱导膜突起和FBP 17如何形成内吞小管，2）确定CIP 4如何诱导膜突起和FBP 17如何形成内吞小管。 膜的断裂导致早熟的丝状伪足形成和神经突的生长，3）揭示了空间和 内源性标记CIP 4和FBP 17在小鼠系中的时间表达模式和4）解析CIP 4和 FBP 17在体内皮质发育中的功能。这项工作将提供基本的见解如何蛋白质， 桥接膜和肌动蛋白细胞骨架功能，以调节过程生长和皮质神经元迁移 哺乳动物大脑的早期发育。CIP 4和FBP 17与亨廷顿病有关， 几种形式的癌症，强调了确定这些蛋白质在发展中国家的功能的重要性。 大脑皮层

Breaking neuronal symmetry is a fundamental process in the formation of a polarized neuron. Neurons in the developing cerebral cortex are born as spherical cells that must extend leading and trailing processes to migrate to their destination in the developing cortical plate. Cortical neurons then extend long axons and dendrites from these processes to create functional circuits. Cortical neuron migration and process extension is critically dependent on the microtubule and actin cytoskeleton, but relatively little is known about how the actin cytoskeleton and plasma membrane are coordinated during these events. Membrane protrusion and invagination are fundamental cellular activities that require coordination of the plasma membrane and underlying actin cytoskeleton. However, there is a dearth of data on how membrane protrusion and invagination are integrated in process outgrowth and neuronal migration. The F-BAR superfamily of proteins are involved in membrane curvature sensing and deformation through their F-BAR domain, positioning them as potentially important players in both membrane invagination and protrusion. Structurally, they form a curved dimer that self-multimerizes around endocytic vesicles, causing their elongation into tubules. The CIP4 family of proteins (CIP4, FBP17 and TOCA1) is a group of F-BAR proteins that 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. Lamellipodial-like protrusions induced by CIP4 strongly inhibit neurite outgrowth in culture. Conversely, we find that a close family member, FBP17, forms endocytic tubules in developing cortical neurons and promotes prominent filopodia formation, resulting in precocious neurite outgrowth. In this proposal we will test the novel hypothesis that protrusion through CIP4 and invagination through FBP17 act in opposing manners to regulate cortical neuron migration and process formation in the developing cortex. Specifically, we will: 1) Determine how CIP4 induces membrane protrusions and FBP17 forms endocytic tubules, 2) Establish how membrane tubulation results in precocious filopodia formation and neurite outgrowth, 3) Reveal the spatial and temporal expression pattern of endogenously-labeled CIP4 and FBP17 in mouse lines and 4) Resolve CIP4 and FBP17 function in cortical development in vivo. This work will provide fundamental insights into how proteins that bridge the membrane and actin cytoskeleton function to regulate process outgrowth and cortical neuron migration in the early developing mammalian brain. CIP4 and FBP17 have been implicated in Huntington's disease and several forms of cancer, underscoring the importance of determining the function of these proteins in the developing cerebral cortex.