Spatial organization of actin polymerizaton during axon guidance.

轴突引导期间肌动蛋白聚合的空间组织。

• 批准号: 8423619
• 负责人: CHRISTOPHER C QUINN
• 金额: $ 7.39万
• 依托单位: UNIVERSITY OF WISCONSIN MILWAUKEE
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-01 至 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8423619
• 关键词: ABI1 gene; Actins; Address; Axon; Breast Cancer Cell; Caenorhabditis elegans; Cancer Patient; Cell physiology; Cells; Complex; Cues; Cytoskeletal Filaments; Cytoskeleton; Data; Data Reporting; Dendrites; Development; Developmental Biology; Diagnosis; Event; Failure; Future; Gene Expression Profile; Genomics; Goals; Growth; Growth Cones; Homologous Gene; Investigation; Knowledge; Lead; Link; Malignant Neoplasms; Mediating; Medicine; Mental disorders; Nervous system structure; Neurons; Outcome Study; Patients; Principal Investigator; Process; Proteins; Publishing; RNA Interference; Recruitment Activity; Regulation; Research; Role; Side; Signal Transduction; Source; Staging; System; Work; abstracting; axon growth; axon guidance; base; cancer cell; cell motility; developmental disease; extracellular; genetic regulatory protein; in vivo; insight; migration; nervous system disorder; neuronal growth; polymerization; presynaptic; receptor; response; ABI1 gene; Actins; Address; Axon; Breast Cancer Cell; Caenorhabditis elegans; Cancer Patient; Cell physiology; Cells; Complex; Cues; Cytoskeletal Filaments; Cytoskeleton; Data; Data Reporting; Dendrites; Development; Developmental Biology; Diagnosis; Event; Failure; Future; Gene Expression Profile; Genomics; Goals; Growth; Growth Cones; Homologous Gene; Investigation; Knowledge; Lead; Link; Malignant Neoplasms; Mediating; Medicine; Mental disorders; Nervous system structure; Neurons; Outcome Study; Patients; Principal Investigator; Process; Proteins; Publishing; RNA Interference; Recruitment Activity; Regulation; Research; Role; Side; Signal Transduction; Source; Staging; System; Work; abstracting; axon growth; axon guidance; base; cancer cell; cell motility; developmental disease; extracellular; genetic regulatory protein; in vivo; insight; migration; nervous system disorder; neuronal growth; polymerization; presynaptic; receptor; response

DESCRIPTION (provided by applicant): Many of the intracellular components that allow neuronal growth cones to interpret and respond to extracellular guidance cues have been identified, but we lack an understanding of how these components function to establish asymmetry in the growth cone. C. elegans provides an excellent system to address this question, because it is possible to observe the localization of proteins within a neuron as it responds to a guidance cue in vivo. In the HSN neuron of C. elegans, UNC-40 (also known as DCC) receptor becomes asymmetrically localized to the side of the cell closest to the source of the UNC-6 (also known as netrin) guidance cue. This in turn, leads to asymmetric recruitment of MIG-10 (also known as lamellipodin), which has an outgrowth-promoting activity, thereby causing outgrowth towards the source of UNC-6 guidance cue. The outgrowth-promoting activity of MIG-10 is thought to result from actin polymerization, but the link between MIG-10 and the actin cytoskeleton is not understood. The objective of this proposal is to determine how MIG-10 links to the actin cytoskeleton to cause a directional outgrowth-promoting activity. Our hypothesis is that MIG-10 (lamellipodin) promotes directional outgrowth by asymmetrically recruiting the WAVE actin regulatory complex. It is expected that the results from these studies will allow us to build an understanding of how signaling complexes can spatially organize actin regulatory proteins to promote growth in response to axon guidance cues. Furthermore, it is likely that the results of these studies will have broader significance because UNC-40 and MIG-10 have been implicated in a wide variety of other morphogenetic events and emerging evidence suggests that asymmetric localization is a key part of their roles in these processes. PUBLIC HEALTH RELEVANCE: Normal axon guidance is required for the development of a functional nervous system and genetically encoded disruptions in this process can underlie mental and neurological disorders. Thus, the proposed research will lead to the development of fundamental knowledge that could impact the diagnosis and treatment of these developmental disorders.

描述（由申请人提供）：已经确定了许多细胞内成分，这些细胞内成分允许神经元生长锥解释和响应细胞外引导提示，但是我们对这些成分在生长锥中建立不对称性的功能缺乏了解。秀丽隐杆线虫提供了一个出色的系统来解决这个问题，因为可以观察神经元内蛋白质的定位，因为它可以在体内响应指导提示。在秀丽隐杆线虫的HSN神经元中，UNC-40（也称为DCC）受体不对称地位于最接近UNC-6（也称为Netrin）指南的细胞侧。反过来，这导致MIG-10（也称为lamellipodin）的不对称募集，该募集具有促进活性的活性，从而导致对UNC-6指南的来源产生生长。 MIG-10的促进活性被认为是肌动蛋白聚合引起的，但是MIG-10与肌动蛋白细胞骨架之间的联系尚不清楚。该提案的目的是确定MIG-10如何与肌动蛋白细胞骨架引起定向生长的促进活性。我们的假设是MIG-10（Lamellipodin）通过不对称募集波肌动蛋白调节复合物来促进方向生长。预计这些研究的结果将使我们能够对信号传导复合物如何在空间组织肌动蛋白调节蛋白中如何促进轴突引导提示促进生长。此外，这些研究的结果可能具有更广泛的意义，因为UNC-40和MIG-10与各种其他形态发生事件有关，并且新出现的证据表明，不对称定位是其在这些过程中角色的关键部分。 公共卫生相关性：在此过程中发展功能性神经系统和遗传编码的破坏需要正常的轴突指导，这可能是心理和神经系统疾病的基础。因此，拟议的研究将导致基本知识的发展，这可能会影响这些发育障碍的诊断和治疗。