Role of Calsyntenin in Axon Guidance

Calsyntenin 在轴突引导中的作用

• 批准号: 8125538
• 负责人: Olga Y Ponomareva
• 金额: $ 3.54万
• 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 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8125538
• 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

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). PUBLIC HEALTH RELEVANCE: Project Narrative An understanding of the complex processes involved in promoting and inhibiting neuronal axon growth, and the functions of molecules that guide axons to their correct targets will be crucial for understanding disorders of neural development. Knowledge of these mechanisms will also aid in our understanding of the conditions under which axon regeneration can occur.

描述(申请人提供)：为了建立一个有功能的神经系统，轴突沿着已建立的路径投射很长的距离，以到达它们适当的连接。影响轴突生长和引导的因素对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，表现出不同的投射模式和行为。一个细胞的轴突表现出如此不同的行为的机制尚不清楚。最近，转录因子被证明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同源结构域(LIM-HD)转录因子会导致外周轴突的丢失，而不会影响中枢轴突。这一发现表明，LIM-HD转录因子在中枢和外周感觉神经元的形成中发挥不同的作用。我们进行了微阵列以确定LIM-HD的下游靶点。在这里，我的目标是了解我们的微阵列所确定的这些靶点之一的功能，即跨膜蛋白Calsyntenin。Calsyntenin在体内的功能尚不清楚，但已被证明在细胞培养中调节淀粉样前体蛋白(APP)的运输，并介导囊泡货物与Kinesin-1的结合。这些功能表明，Calsyntenin可能参与了神经元成分的运输和选择性靶向--这一过程对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，此时轴突被引导到它们的靶点，然而，它在神经元发育中的作用尚不清楚。我们的初步数据表明，Calsyntenin对外周感觉轴突的投射有特定的影响，而对中枢轴突没有影响。这种表型与LIM-HD抑制类似，进一步表明Calsyntenin是LIM-HD的下游靶点。在拟议的实验中，我将进一步表征Calsyntenin对感觉神经轴突生长的影响(目标1)，确定Calsyntenin是否差异地输送到感觉神经轴突的中枢和外周组件(目标2)，并确定Calsyntenin的哪些功能结构域负责选择性外周轴突表型(目标3)。 公共卫生相关性：项目叙事了解促进和抑制神经元轴突生长的复杂过程，以及引导轴突到达正确目标的分子的功能，对于理解神经发育障碍至关重要。对这些机制的了解也将有助于我们理解轴突再生的条件。