Role of Calsyntenin in Axon Guidance

Calsyntenin 在轴突引导中的作用

• 批准号: 8645766
• 负责人: Olga Y Ponomareva
• 金额: $ 0.94万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-04-01 至 2014-07-01
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8645766
• 关键词: Address; Affect; Afferent Neurons; Amyloid beta-Protein Precursor; Autistic Disorder; Axon; Behavior; Binding; Brain; Caring; Cell Culture Techniques; Cells; Chimeric Proteins; Cues; Data; Development; Disease; Docking; Dominant-Negative Mutation; Embryo; Environment; Exhibits; Genes; Genetic; Goals; Growth; Human Genetics; Image; In Situ Hybridization; Individual; Integral Membrane Protein; Kinesin; Knowledge; Lead; Life; Mediating; Messenger RNA; Microarray Analysis; Molecular; Morphology; Movement; Mus; Nervous system structure; Neurologic; Neurons; Optics; Pathology; Pathway interactions; Pattern; Peripheral; Phenotype; Process; Proteins; Role; Schizophrenia; Sensory; Signal Transduction; Staging; Stereotyping; Study models; Synapses; System; Testing; Vertebrates; Zebrafish; axon growth; axon guidance; cell motility; cofactor; genetic manipulation; homeodomain; in vivo; in vivo imaging; insight; nervous system development; neuron development; overexpression; protein transport; research study; trafficking; transcription factor

DESCRIPTION (provided by applicant): To establish a functional nervous system, axons project long distances along established pathways to reach their proper connections. Factors that influence the growth and guidance of axons are critical for the proper development of the brain, but the mechanisms by which these factors function in vivo are not well understood. We are using the optically transparent embryonic zebrafish to study and visualize how sensory neurons are guided in their natural environment. Zebrafish sensory neurons have a stereotyped morphology with two types of axons which exhibit distinct projection patterns and behaviors. Mechanisms by which axons from one cell can exhibit such different behaviors are not known. Recently, transcription factors have been shown to partially control the specific projection patterns of some axons. In zebrafish sensory neurons, inhibition of LIM-homeodomain (LIM-HD) transcription factors causes a loss of peripheral axons, without an effect on central axons. This finding suggests that LIM-HD transcription factors act differently on the formation of central and peripheral sensory neurons. We performed a microarray to identify downstream targets of LIM-HDs. Here, I aim to understand the function of one of these targets as identified by our microarray, a transmembrane protein Calsyntenin. The in vivo function of Calsyntenin is not known, however, it has been shown to regulate the trafficking of Amyloid Precursor Protein (APP) and to mediate vesicular cargo binding to kinesin-1 in cell culture. These functions suggest that Calsyntenin may be involved in trafficking and selective targeting of neuronal components - processes that are vital for axon outgrowth and guidance. Calsyntenin is expressed during the development of the nervous system at a stage when axons are guided to their targets, however, its role in neuronal development is not known. Our preliminary data suggest that Calsyntenin exerts a specific effect on the projections of peripheral sensory axons, without an effect on central axons. This phenotype is similar to that of LIM-HD inhibition, further suggesting that Calsyntenin is a downstream target of LIM-HD. In the proposed experiments, I will further characterize the effect of Calsyntenin on sensory axon growth (Aim 1), determine whether Calsyntenin is differentially trafficked to central vs. peripheral components of sensory axons (Aim 2), and identify which functional domains of Calsyntenin are responsible for the selective peripheral axon phenotype (Aim 3).

描述（由申请人提供）：为了建立功能性神经系统，轴突沿着建立的途径长距离投影以达到其适当的连接。影响轴突生长和指导的因素对于大脑的正确发育至关重要，但是这些因素在体内发挥作用的机制尚不清楚。我们正在使用光学透明的胚胎斑马鱼来研究和可视化感觉神经元如何在其自然环境中引导。斑马鱼感觉神经元具有刻板印象的形态，具有两种类型的轴突，它们表现出独特的投影模式和行为。尚不清楚轴突通过一个细胞表现出这种不同行为的机制。最近，已显示转录因子部分控制某些轴突的特定投影模式。在斑马鱼感觉神经元中，抑制林 - 瘤域（LIM-HD）转录因子会导致外周轴突丧失，而对中央轴突产生影响。这一发现表明，LIM-HD转录因子对中央和周围感觉神经元的形成作用不同。我们进行了一个微阵列以识别LIM-HD的下游目标。在这里，我的目标是了解这些靶标之一的功能，如我们的跨膜蛋白Calsyntenin所确定的。然而，尚不清楚Calsyntenin的体内功能，已证明它可以调节淀粉样蛋白前体蛋白（APP）的运输，并介导细胞培养中的囊泡货物与动蛋白-1的结合。这些功能表明，Calsyntenin可能参与了贩运和选择性靶向神经元成分 - 对于轴突生长和指导至关重要的过程。在轴突被引导到目标的阶段，在神经系统的发展过程中表达了Calsyntenin，但是，其在神经元发育中的作用尚不清楚。我们的初步数据表明，Calsyntenin对外围感觉轴突的投影产生了特定的影响，没有对中央轴突的影响。该表型与LIM-HD抑制相似，进一步表明Calsyntenin是LIM-HD的下游靶标。在拟议的实验中，我将进一步表征Calsyntenin对感觉轴突生长的影响（AIM 1），确定Calsyntenin是否差异地运输到感觉轴突的中心与外围成分（AIM 2）（AIM 2），并确定Calsyntenin的哪个功能领域，负责选择性外围轴突轴突均质型（AIL AIM 3）。