F-BAR proteins in neuronal migration and process formation

F-BAR 蛋白在神经元迁移和过程形成中的作用

基本信息

批准号：
10317364
负责人：
Erik W Dent
金额：
$ 38.88万
依托单位：
UNIVERSITY OF WISCONSIN-MADISON
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-08-01 至 2026-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10317364
关键词：
Actin-Binding Protein Actins Address Affect Axon Binding Brain CRISPR/Cas technology Cell membrane Cell physiology Cells Cerebral cortex Cytoskeleton Data Dendrites Destinations Development Electroporation Endocytic Vesicle Endocytosis Event Family Family member Filopodia Gap Junctions Huntington Disease Immunoprecipitation Label Link Malignant Neoplasms Mammalian Cell Mass Spectrum Analysis Membrane Microfilaments Microtubules Molecular Morphology Mus Nerve Degeneration Nervous System Physiology Neurites Neurons Pattern Peripheral Play Polymers Positioning Attribute Process Protein Family Proteins Publishing RNA Splicing Reagent Reporter Research Role Set protein Signal Pathway Structure TRIP10 gene Techniques Testing Variant Vesicle Work cell type design dimer dosage experimental study human disease in utero in vivo insight internal control knock-down migration nervous system development neuron development neuronal replacement novel novel strategies overexpression polymerization protein function rho GTP-Binding Proteins

项目摘要

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.

破坏神经元对称性是形成偏振神经元的基本过程。神经元中的神经元发育的大脑皮层是作为球形细胞诞生的，必须扩展前导和落后过程才能迁移到他们在发育中的皮质板中的目的地。然后，皮质神经元从长轴突和树突上延伸这些过程以创建功能电路。皮质神经元迁移和过程扩展非常重要取决于微管和肌动蛋白细胞骨架，但对肌动蛋白细胞骨架的了解相对较少在这些事件中，质膜和质膜是协调的。膜突出和内陷是需要质膜和基础肌动蛋白细胞骨架的基本细胞活性。但是，缺乏有关膜突出和内陷如何整合到过程中的数据生长和神经元迁移。蛋白质的F-BAR超家族参与膜曲率感应并通过其F-bar域变形，将它们定位为两种膜上潜在的重要参与者不知不觉和突出。从结构上讲，它们形成了弯曲的二聚体，该二聚体在内吞围绕内吞囊泡，导致其伸长到小管中。 CIP4蛋白质家族（CIP4，FBP17和TOCA1）是一组结合肌动蛋白相关蛋白的F-BAR蛋白。像其他F-Bar蛋白一样，CIP4家族被认为是主要在膜不足和内吞作用中起作用，但我们最近的工作已与CIP4有关膜突出。由CIP4诱导的层状叶状类突出强烈抑制神经突的生长文化。相反，我们发现一个亲密的家庭成员FBP17形成了内吞小管，形成了皮质神经元并促进突出的丝状肌形成，导致早熟的神经突生长。在这个建议中，我们将测试新的假设，即通过CIP4突出并通过FBP17起作用。调节发展皮层中皮质神经元迁移和过程形成的礼节。具体来说，我们将： 1）确定CIP4如何诱导膜突起，FBP17形成内吞小管，2）建立如何建立膜管会导致早熟的丝状肌形成和神经突生长，3）揭示了空间和内源标记的CIP4和FBP17的时间表达模式，4）解决CIP4和 FBP17体内皮质发育中的功能。这项工作将提供有关该蛋白质如何的基本见解桥接膜和肌动蛋白细胞骨架功能，以调节过程出生和皮质神经元迁移在早期发育的哺乳动物大脑中。 CIP4和FBP17与亨廷顿氏病有关几种形式的癌症，强调了确定这些蛋白质在发育中的功能的重要性大脑皮层。