Determination of neuronal fates in visual cortex

视觉皮层神经元命运的测定

• 批准号: 8217221
• 负责人: Susan K McConnell
• 金额: $ 40.72万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-02-01 至 2014-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8217221
• 关键词: Adult; Affect; Affective; Alleles; Autistic Disorder; Axon; Cell Adhesion Molecules; Cell Fate Control; Cell Transplants; Cells; Cerebral cortex; Chromatin; Cognition; Cognitive; Collaborations; Cues; DNA-Binding Proteins; Defect; Destinations; Development; Disease; Dyslexia; Ectopic Expression; Environment; Epilepsy; Funding; Gene Expression; Gene Expression Profile; Gene Targeting; Genes; Genetic; Germany; Goals; Immigration; Instruction; Ion Channel; Mental Health; Methods; Mitotic; Molecular; Morphology; Mus; Mutant Strains Mice; Mutation; Neurons; Pathway interactions; Pattern; Plastics; Positioning Attribute; Process; Property; Repression; Research; Role; Schizophrenia; Series; Signal Transduction; Site; Stem cells; Testing; Time; To specify; Transplantation; Ventricular; Vision; Visual Cortex; axon guidance; cDNA Arrays; genome-wide; mutant; neurogenesis; novel; progenitor; programs; public health relevance; receptor; research study; response; transcription factor

DESCRIPTION (provided by applicant): During development, progenitor cells produce a large diversity of young neurons that migrate away from their site of origin and establish distinct identities, including the formation of specific connections. The major aim of this research is to understand the cellular and molecular processes by which young neurons in the mammalian visual cortex achieve their adult identities during development, migrate to appropriate positions, and form axonal connections with appropriate target cells. Defects in the formation and elaboration of cortical circuits have fundamental implications for vision, cognition, and mental health, since defects in the migration and connectivity of cortical neurons are associated with a variety of disorders including epilepsy, dyslexia, schizophrenia, bipolar affective illness, and autism. The goals of our research are to identify the genes that regulate neurogenesis in the visual cortex and to understand how they affect the formation of cortical circuitry. We will explore the following specific issues: (1) Satb2 is a DNA-binding protein that regulates chromatin organization and is expressed in callosal projection neurons. To explore the role of Satb2 in fate determination, will analyze the axonal projections, electrophysiological properties, and gene expression patterns of neurons in mice with a conditional mutation of Satb2. (2) We will identify and characterize the downstream effectors of Satb2 and their roles in regulating the lamination and axonal projections of callosal projection neurons. (3) We found previously that the transcription factors Fezf2 and Ctip2 regulate the identity of subcortical projection neurons, and that Fezf2, Ctip2 and Satb2 interact genetically to form two mutually repressive pathways. We will explore how neurons decide between a subcortical vs. callosal projection neuron fate by exploring the genetic interactions between the Fezf2/Ctip2 and Satb2 pathways. (4) We will use transplantation methods to explore the acquisition of a subcortical vs. callosal projection neuron identity. By transplanting presumptive layer 6 cells into layer 2/3, and vice versa, we will ascertain whether and over what period of time a young cortical neuron can respond to local fate- inducing cues and alter its normal layer-specific identity, as assessed by its dendritic morphology, local and long distance axonal projections, and pattern of layer-specific gene expression. PUBLIC HEALTH RELEVANCE: Defects in the formation and elaboration of cortical circuits have fundamental implications for vision, cognition, and mental health, since defects in the migration and connectivity of cortical neurons are associated with a variety of disorders including epilepsy, dyslexia, schizophrenia, bipolar affective illness, and autism. The goals of our research are to identify the genes that regulate neurogenesis in the visual cortex and to understand how they affect the formation of cortical circuitry.

描述（由申请人提供）：在发育过程中，祖细胞产生大量多样性的年轻神经元，这些神经元从其起源部位迁移并建立不同的身份，包括形成特定的连接。本研究的主要目的是了解哺乳动物视皮层中的年轻神经元在发育过程中实现其成年身份，迁移到适当的位置，并与适当的靶细胞形成轴突连接的细胞和分子过程。皮层回路的形成和加工缺陷对视觉、认知和心理健康具有根本性的影响，因为皮层神经元的迁移和连接缺陷与各种疾病有关，包括癫痫、阅读障碍、精神分裂症、双相情感疾病和自闭症。我们研究的目标是确定调节视觉皮层神经发生的基因，并了解它们如何影响皮层回路的形成。我们将探讨以下具体问题：（1）Satb 2是一个DNA结合蛋白，调节染色质的组织和表达在胼胝体投射神经元。为了探索Satb 2在命运决定中的作用，将分析Satb 2条件突变小鼠神经元的轴突投射，电生理特性和基因表达模式。(2)我们将确定和表征Satb 2的下游效应子及其在调节胼胝体投射神经元的层压和轴突投射中的作用。(3)我们以前发现，转录因子Fezf 2和Ctip 2调节皮质下投射神经元的身份，并且Fezf 2、Ctip 2和Satb 2在遗传上相互作用形成两个相互抑制的通路。我们将探索神经元如何决定皮质下与胼胝体投射神经元的命运，通过探索Fezf 2/Ctip 2和Satb 2通路之间的遗传相互作用。(4)我们将使用移植的方法来探讨收购皮质下与胼胝体投射神经元的身份。通过将假定的第6层细胞移植到第2/3层中，反之亦然，我们将确定年轻皮层神经元是否以及在多长时间内可以响应于局部命运诱导线索并改变其正常的层特异性身份，如通过其树突形态、局部和长距离轴突投射以及层特异性基因表达模式所评估的。 公共卫生相关性：皮层回路的形成和加工缺陷对视觉、认知和心理健康具有根本性的影响，因为皮层神经元的迁移和连接缺陷与各种疾病有关，包括癫痫、阅读障碍、精神分裂症、双相情感疾病和自闭症。我们研究的目标是确定调节视觉皮层神经发生的基因，并了解它们如何影响皮层回路的形成。