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: 9767214
• 负责人: JAMES DAVID JONTES
• 金额: $ 38.5万
• 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/9767214
• 关键词: 3-Dimensional; Address; Affect; Architecture; Axon; Behavior; Behavioral; Brain Diseases; Cell Adhesion Molecules; Cells; Clonal Expansion; Code; Data; Defect; Dendrites; Development; Developmental Process; Epilepsy; Event; Exhibits; Family; Family member; Female; Gene Family; Genes; Genetic; Goals; Health; Human; Image; Impairment; 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; Systems Development; Tectum Mesencephali; Testing; Therapeutic; Transgenic Organisms; Visual; Visual Pathways; Visual system structure; Work; Zebrafish; autism spectrum disorder; base; design; differential expression; gene product; in vivo; in vivo calcium imaging; insight; member; migration; mutant; neural circuit; neurodevelopment; neuroepithelium; neurogenesis; neuron development; progenitor; programs; 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.

摘要 感知和行为的神经回路在发育过程中通过以下方式组装： 复杂和协调的过程，包括神经发生和迁移，轴突和树突的延伸， 树枝化和突触形成。反过来，保守的遗传程序协调了这些动态的 发展过程。虽然在识别对人类免疫系统重要的基因方面已经取得了很大进展， 神经功能，将基因产物的作用与神经结构的组装联系起来的机制， 对功能的了解很少。为了解决这个重要的问题，我们已经产生了斑马鱼突变体， 和几种δ-pCDHS的转基因系，这些δ-pCDHS是进化上保守的嗜同性细胞粘附分子， 在发育中的神经系统中强烈表达。我们表明δ-pCDHS在径向内表达 发育中的斑马鱼视顶盖中的神经元柱，并且这些柱内的神经元是 从一个或少数祖先衍生的兄弟姐妹。pcdh 19的损失使柱状 pcdh 19表达神经元的组织，表明原钙粘蛋白功能是柱 上维护此外，pcdh 19突变体在视觉引导行为方面表现出缺陷。该提案测试了 假设δ-pcdh的共同遗传赋予一列神经元同一性， 差异表达δ-pCDHS定义了组织顶盖回路的代码，对神经功能至关重要 和行为。具体来说，我们将绘制表达单个δ-pcdhs的神经元的3D分布，用于 体内时间推移，以确定柱形成过程中δ-pCDHS的细胞作用，并使用体内钙 成像以确定δ-PCDH缺失对神经活动模式发展的影响。本研究将 揭示了神经组织的一个基本方面，并对神经组织产生了重要的新见解。 基因之间的关系，神经结构的发展和一系列神经系统的起源， 归因于细胞粘附原钙粘蛋白亚家族成员的神经发育障碍 分子。