Glial control of sensory neuron receptive-ending shape and function

神经胶质控制感觉神经元接受末端的形状和功能

• 批准号: 9239046
• 负责人: Shai Shaham
• 金额: $ 37.08万
• 依托单位: ROCKEFELLER UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-12-01 至 2017-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9239046
• 关键词: Actins; Address; Affect; Afferent Neurons; Anatomy; Animals; Apoptotic; Astrocytes; Behavior; Binding; Biological Assay; Blindness; Caenorhabditis elegans; Cell Shape; Cell physiology; Cells; Clinical; Cues; Cyclic GMP; Dendritic Spines; Dependence; Development; Disease; Genes; Genetic Screening; Genetic study; Goals; Growth; Guanylate Cyclase; Human; Ions; Lead; Learning; Lesion; Mammals; Mediating; Memory; Microglia; Molecular; Molecular Biology; Morphogenesis; Morphology; Motor; Mutation; Nematoda; Nervous System Physiology; Nervous system structure; Neuroglia; Neurons; Organ; Organism; Output; Pathology; Pathway interactions; Pattern; Phosphatidylserines; Photoreceptors; Physiology; Play; Proteins; Recruitment Activity; Regulation; Reporting; Role; Schwann Cells; Sensory; Shapes; Signal Pathway; Signal Transduction; Site; Specificity; Stimulus; Structure; Structure of retinal pigment epithelium; Synapses; Temperature; Temperature Sense; Tertiary Protein Structure; Testing; Thrombospondin 1; Thrombospondins; Usher Syndrome; Vertebral column; Vertebrates; Vesicle; cellular microvillus; congenital deafness; experience; extracellular; inherited retinal degeneration; inhibitor/antagonist; mutant; nervous system disorder; neurotransmission; novel; organ growth; overexpression; phosphatidylserine receptor; photoreceptor cell outer segment; postsynaptic neurons; protein function; receptor; synaptogenesis; uptake

Our long-term goal is to understand glial control of neuron receptive-ending shape and function. Neurons detect external stimuli through specialized dendritic receptive endings. Receptive-endings are malleable and regulate neuronal output. For example, neurons receive information at dendritic spines. Remodeling of spine shape occurs in development and is effected by experience. Perturbations in spine shape are associated with neurological disorders, suggesting that spine morphogenesis may play key roles in nervous system function. Like spines, receptive endings of sensory neurons are remodeled in development and by experience. Photoreceptor cell outer segments, for example, are turned over and rebuilt daily. Perturbation of sensory receptive-ending shape leads to sensory deficits and is a common pathology in sensory diseases. Despite clear clinical importance, the questions of how sensory cell shapes are regulated, how shape affects function, and how glia-neuron interactions control sensory neuron receptive-ending shape, have not been extensively addressed. The nematode C. elegans is an excellent organism in which to study glia-neuron interactions controlling sensory receptive-ending morphogenesis and plasticity. Sensory organ anatomy, physiology, and molecular biology are conserved from C. elegans to humans, making the nematode an exciting arena for revealing general principles of sensory organ development and function. The C. elegans AFD neuron mediates temperature sensation and cultivation-temperature memory. We showed that AFD receptive- ending shape is dynamically controlled and uncovered a novel signaling pathway guiding these changes. Shape changes require the receptor guanylyl cyclase GCY-8, controlling cGMP levels in AFD. High cGMP blocks receptive-ending extension, and this is overcome by overexpression of the actin regulator WASP-1. Loss of the glial transporter KCC-3, which specifically surrounds AFD, also blocks microvilli growth, by removing Cl- ions from an extracellular microdomain around AFD. Cl- ions function as novel direct inhibitors of GCY-8 cyclase activity. We further found that glia engulf and take up AFD neuron receptive-ending fragments, and that engulfment is required for AFD neuron function. Our results reveal glia-neuron interaction pathways determining neuron receptive-ending morphology, components of which are conserved in mammals. We propose three aims: (1) We will determine how glia form a unique microdomain around AFD neurons that is distinct from domains around other neurons. (2) We will study the role of glial FIG-1/thrombospondin in engulfment of AFD receptive endings and AFD neuron shape. (3) We will study the role of the phosphatidylserine receptor PSR-1 in engulfment of AFD endings and shape.

我们的长期目标是了解神经元接受形状和功能的神经胶质控制。 神经元通过专门的树突状接受末端检测外部刺激。接受末端是 可延展和调节神经元输出。例如，神经元在树突状棘上接收信息。 脊柱形状的重塑发生在开发中，并由经验产生。扰动 脊柱形状与神经系统疾病有关，表明脊柱形态发生可能会发挥作用 神经系统功能中的关键作用。像刺一样，感觉神经元的接受结局被重塑 在发展和经验中。例如，光感受器细胞外部段被移交 每天重建。感觉接受形状的扰动导致感觉缺陷，是一个 感觉疾病中的常见病理。尽管临床意义明显，但有关如何的问题 感觉细胞形状受调节，形状如何影响功能以及神经胶质神经元相互作用如何控制 感觉神经元接受形状尚未得到广泛解决。线虫C。 秀丽隐杆线虫是一个很好的生物体，可以在其中研究控制感觉的神经胶质 - 神经元相互作用 接受的形态发生和可塑性。感觉器官解剖学，生理和分子 生物学从秀丽隐杆线虫到人类保存，使线虫成为令人兴奋的舞台 揭示感觉器官发育和功能的一般原则。秀丽隐杆线虫AFD神经元 介导温度感觉和培养温度的记忆。我们表明AFD接受 - 结束形状是动态控制的，并发现了一个新颖的信号通路，以指导这些 更改。形状的变化需要受体鸟叶基环酶GCY-8，控制AFD中的CGMP水平。 高CGMP阻止了接收到的延伸，这是通过肌动蛋白过表达克服的 调节器WASP-1。特别围绕AFD的神经胶质转运蛋白KCC-3的丢失也阻塞 通过从AFD周围的细胞外微区域中去除cl菌的生长。 Cl-iros功能 作为GCY-8环酶活性的新型直接抑制剂。我们进一步发现Glia吞噬并占用AFD 神经元接受的片段，AFD神经元功能需要吞噬。我们的 结果揭示了神经元的相互作用途径决定神经元接受形态， 其成分在哺乳动物中是保守的。我们提出三个目标：（1）我们将确定如何 Glia在AFD神经元周围形成独特的微域，该域与其他域不同 神经元。 （2）我们将研究神经胶质图1/血小板素在AFD接受吞噬中的作用 结尾和AFD神经元形状。 （3）我们将研究磷脂酰丝氨酸受体PSR-1在 AFD结尾和形状的吞没。