Protocadherins in zebrafish visual system development

原钙粘蛋白在斑马鱼视觉系统发育中的作用

• 批准号: 9159550
• 负责人: JAMES DAVID JONTES
• 金额: $ 34.45万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-01 至 2021-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9159550
• 关键词: Address; Affect; Architecture; Autistic Disorder; Axon; Behavior; Behavioral; Brain Diseases; Calcium; Cell Adhesion Molecules; Cells; Clonal Expansion; Code; Data; Defect; Dendrites; Development; Developmental Process; Epilepsy; Event; Exhibits; Family; Family member; Female; Gene Family; Genes; Genetic; Genetic Programming; Goals; Health; Human; Image; In Situ Hybridization; Incidence; Individual; Infant; Larva; Lead; Lesion; Light; Link; Maintenance; Maps; Mediating; Modeling; Molecular; Mutation; Nervous system structure; Neural Cell Adhesion Molecules; Neurodevelopmental Disorder; Neuroepithelial; Neuronal Dysfunction; Neurons; Neurophysiology - biologic function; Pattern; Perception; Process; Radial; Research; Role; Schizophrenia; Siblings; Stem cells; Tectum Mesencephali; Testing; Therapeutic; Transgenic Organisms; Visual; Visual Pathways; Visual system structure; Work; Zebrafish; base; design; differential expression; gene product; in vivo; insight; member; migration; mutant; neural circuit; neurodevelopment; neuroepithelium; neurogenesis; neuron development; progenitor; protocadherin 19; relating to nervous system; superior colliculus Corpora quadrigemina; synaptogenesis; two-photon; vision development; zebrafish development

ABSTRACT The neural circuits underlying perception and behavior are assembled during development through intricate and coordinated processes that include neurogenesis and migration, axon and dendrite extension and arborization and synapse formation. In turn, conserved genetic programs orchestrate these dynamic developmental processes. While much progress has been made in identifying genes that are important for neural function, the mechanisms linking the action of gene products to the assembly of neural architecture and to function are poorly understood. To address this important question, we have generated zebrafish mutants and transgenic lines for several δ-pcdhs, evolutionarily conserved homophilic cell adhesion molecules that are strongly expressed in the developing nervous system. We show that δ-pcdhs are expressed within radial columns of neurons in the developing zebrafish optic tectum, and that the neurons within these columns are siblings derived from one or a small number of progenitors. Loss of pcdh19 degrades the columnar organization of pcdh19-expressing neurons, indicating that protocadherin function is required for column maintenance. Moreover, pcdh19 mutants exhibit defects in visually guided behaviors. This proposal tests the hypothesis that the shared inheritance of a δ-pcdh confers an identity to a column of neurons, and that differential expression δ-pcdhs defines a code for organizing tectal circuitry and is essential for neural function and behavior. Specifically, we will map the 3D distribution of neurons expressing individual δ-pcdhs, use in vivo timelapse to determine the cellular roles of δ-pcdhs during column formation, and use in vivo calcium imaging to determine the effects of δ-pcdh loss on the development of neural activity patterns. This study will shed light on a fundamental aspect of neural organization and generate essential new insights into the relationships between genes, the development of neural architecture and the origins of a range of neurodevelopmental disorders attributed to members of the protocadherin subfamily of cell adhesion molecules.

抽象的 在开发过程中，通过 复杂和协调的过程，包括神经发生和迁移，轴突和树突延伸以及 树木化和突触形成。反过来，配置的遗传程序会协调这些动态 发展过程。尽管在识别对重要的基因方面取得了很多进展 神经功能，将基因产物的作用与神经结构组装联系起来的机制 功能知之甚少。为了解决这个重要的问题，我们产生了斑马鱼突变体 以及几种Δ-pCDHS的转基因线，进化保守的均电细胞粘附分子 在发育中的神经系统中强烈表达。我们表明Δ-pCDHS在径向内表示 在发育中的斑马鱼视觉处理中神经元的列，这些柱中的神经元是 兄弟姐妹来自一个或少数祖细胞。 PCDH19的损失降低了柱子 表达PCDH19的神经元的组织，表明列需要协议蛋白功能 维护。此外，PCDH19突变体存在于视觉引导行为中。该建议测试 假设δ-PCDH的共同继承赋予了对神经元列的身份，并且 差异表达Δ-PCDHS定义了组织置直肠电路的代码，对于神经功能至关重要 和行为。特别是，我们将绘制表达单个Δ-PCDH的神经元的3D分布，用于 体内时间元素确定色谱柱形成过程中Δ-PCDH的细胞作用，并在体内使用 成像以确定Δ-PCDH丢失对神经活动模式发展的影响。这项研究会 阐明神经组织的基本方面，并为 基因之间的关系，神经结构的发展和一系列范围的起源 神经发育障碍归因于细胞粘附协议亚科的成员 分子。