Role of Calsyntenin in Axon Guidance

Calsyntenin 在轴突引导中的作用

基本信息

批准号：
8319693
负责人：
Olga Y Ponomareva
金额：
$ 3.19万
依托单位：
UNIVERSITY OF WISCONSIN-MADISON
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-04-01 至 2015-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8319693
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 insight nervous system development neuron development overexpression protein transport research study trafficking transcription factor

项目摘要

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，轴突沿着已建立的路径投射很长的距离以到达适当的连接。影响轴突生长和引导的因素对于大脑的正常发育至关重要，但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在自然环境中是如何被引导的。斑马鱼感觉神经元具有刻板的形态，具有两种类型的轴突，表现出不同的投影模式和行为。一个细胞的轴突表现出这种不同行为的机制尚不清楚。最近，转录因子已被证明可以部分控制某些轴突的特定投射模式。在斑马鱼感觉神经元中，抑制 LIM 同源域 (LIM-HD) 转录因子会导致外周轴突丢失，但不会影响中央轴突。这一发现表明 LIM-HD 转录因子对中枢和外周感觉神经元的形成有不同的作用。我们进行了微阵列来识别 LIM-HD 的下游靶标。在这里，我的目标是了解我们的微阵列所识别的其中一个靶标的功能，即跨膜蛋白 Calsyntenin。 Calsyntenin 的体内功能尚不清楚，但已证明它可以调节淀粉样前体蛋白 (APP) 的运输并介导细胞培养中囊泡货物与驱动蛋白-1 的结合。这些功能表明 Calsyntenin 可能参与神经元成分的运输和选择性靶向，这些过程对于轴突的生长和引导至关重要。 Calsyntenin 在神经系统发育过程中表达，此时轴突被引导至其目标，但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 对周围感觉轴突的投射产生特定影响，但对中央轴突没有影响。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（目标 1），确定 Calsyntenin 是否有差异地运输到感觉轴突的中央和外围组件（目标 2），并确定 Calsyntenin 的哪些功能域负责选择性外周轴突表型（目标 3）。