A novel embryonic transcriptional cascade required for adult social and repetitive behavior

成人社交和重复行为所需的新型胚胎转录级联

基本信息

批准号：
9471054
负责人：
ANTHONY J. WYNSHAW-BORIS
金额：
$ 50.04万
依托单位：
CASE WESTERN RESERVE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-11 至 2022-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9471054
关键词：
Address Adult Affect Age Alleles Animals Behavior Behavior Disorders Behavioral Brain Brain region Cell Differentiation process Cell Proliferation Cell model Cerebral cortex Child Communication impairment Complex Defect Development Diffusion Magnetic Resonance Imaging Disease Down-Regulation Embryo Embryonic Development Fetal Development Genes Genetic Genetic Models Genetic Transcription Growth Human Human Development Knockout Mice Laboratories Life Link Magnetic Resonance Imaging Modeling Molecular Mus Mutant Strains Mice Neonatal Neurons Newborn Infant Pathway interactions Pharmacotherapy Phenotype Publishing Role Series Social Behavior Social Interaction Structure Testing Time United States aging brain autism spectrum disorder beta catenin brain abnormalities brain circuitry brain overgrowth brain size cognitive process fetal frontal lobe imaging study in vivo induced pluripotent stem cell information processing insight interest mental state mouse development mouse model mutant nerve stem cell neural circuit neurogenesis neuropsychiatric disorder novel patient subsets prenatal progenitor repetitive behavior social

项目摘要

PROJECT SUMMARY/ABSTRACT Social interaction is a fundamental behavior in all animal species, but the developmental timing of the social neural circuit formation and the cellular and molecular mechanisms governing its formation are poorly understood. It has been hypothesized that abnormal brain development can cause long-term alterations in brain circuitry that may later manifest in behavioral disorders in the adult. Consistent with this idea, a significant subset (~25-30%) of autism spectrum disorder (ASD) is associated with a transient but significant increase in brain size in the first few years of life, leading to abnormal social and other behaviors. In further support of this hypothesis, we found that Dishevelled Dvl1-/-; Dvl3+/- mutant mice displayed increased neural progenitor cell (NPC) proliferation during embryonic development via dysregulation of a novel β-catenin/BRN2 transcriptional cascade associated with adult social/repetitive behavior and brain abnormalities (Belinson et al. 2016). We hypothesize that the β-catenin/BRN2 transcriptional cascade regulates NPC proliferation and differentiation during brain development of mouse, resulting in normal social behavior. Dysregulation of this cascade results in abnormal social behavior from aberrant neurogenesis during embryogenesis, which selectively disrupts adult brain structure/function. We propose to address this hypothesis in the mouse by employing additional Dvl and Brn2 genetic mouse models, comprehensive behavioral analysis, and state-of- the-art mouse imaging studies, in the following three aims. Aim 1. Determine which pathways downstream of the Dvls are responsible for social/repetitive behaviors and transient embryonic brain enlargement phenotypes. The involvement of β-catenin implicates the canonical Wnt pathway in embryonic brain enlargement, social/repetitive behaviors, and adult brain structure/function. To formally prove this, we will use an allelic series of fluorescently-tagged BAC alleles to genetically determine whether the role of Dvl genes in embryonic brain enlargement, social/repetitive behaviors, and adult brain structure/function is via the canonical and/or non-canonical Wnt pathways in vivo. Aim 2. Determine the spatial/temporal requirements of the β-catenin/BRN2 transcriptional cascade for adult social/repetitive behavior and transient embryonic brain enlargement. We will use conditional alleles for Dvl2 and Brn2 as well as brain-specific Cres to genetically determine the spatial/temporal requirements of the β-catenin/BRN2 transcriptional cascade in embryonic brain enlargement, social/repetitive behaviors, and adult brain structure/function. Aim 3. Determine the newborn, weanling and adult brain regions linked to embryonic brain growth and social/repetitive behavior. Magnetic resonance imaging (MRI) and diffusion tensor imaging (DTI) studies of adult brains of mice studied in Aims 1 and 2 will used to determine newborn (P0), weanling (3 weeks of age) and adult 10-12 weeks of age) brain abnormalities associated with social/repetitive behavior and transient embryonic brain enlargement. These regions will be further investigated.

项目概要/摘要社会互动是所有动物物种的基本行为，但动物的发育时间社会神经回路的形成以及控制其形成的细胞和分子机制很差据了解，大脑发育异常会导致大脑的长期改变。与这一观点相一致的是，大脑回路可能随后在成人的行为障碍中表现出来。自闭症谱系障碍 (ASD) 的子集（~25-30%）与短暂但显着的增加有关生命最初几年的大脑尺寸，导致异常的社交和其他行为进一步支持了这一点。假设，我们发现蓬乱的 Dvl1-/-；Dvl3+/- 突变小鼠表现出神经祖细胞增加 (NPC) 通过新型 β-catenin/BRN2 转录失调调节而在胚胎发育过程中增殖与成人社交/重复行为和大脑异常相关的级联（Belinson et al. 2016）。我们发现 β-catenin/BRN2 转录级联调节 NPC 增殖和小鼠大脑发育过程中的分化，导致正常的社会行为失调。胚胎发生过程中神经发生异常导致级联反应导致异常社会行为，我们建议通过选择性地破坏小鼠的大脑结构/功能来解决这一假设。采用额外的 Dvl 和 Brn2 基因小鼠模型、综合行为分析和状态- 最先进的小鼠成像研究，有以下三个目的。目标 1. 确定 Dvls 下游的哪些路径负责社交/重复行为和短暂的胚胎脑增大表型。β-连环蛋白的参与。暗示经典的 Wnt 通路与胚胎大脑增大、社交/重复行为和成人为了证明这一点，我们将使用荧光标记的 BAC 等位基因的等位基因系列。从遗传学上确定 Dvl 基因是否在胚胎大脑增大、社交/重复性中发挥作用行为和成人大脑结构/功能是通过体内的规范和/或非规范Wnt途径实现的。目标 2. 确定 β-catenin/BRN2 转录级联的空间/时间要求对于成人社交/重复行为和短暂的胚胎大脑扩大，我们将使用有条件的。 Dvl2 和 Brn2 的等位基因以及大脑特异性 Cres 从基因上决定空间/时间 β-连环蛋白/BRN2转录级联在胚胎大脑增大、社交/重复性中的要求行为和成人大脑结构/功能。目标 3. 确定与胚胎大脑生长相关的新生儿、断奶和成人大脑区域以及社交/重复行为磁共振成像（MRI）和扩散张量成像（DTI）研究。目标 1 和 2 中研究的小鼠成年大脑的样本将用于确定新生儿 (P0)、断奶（3 周龄）和 10-12 周龄的成人）与社交/重复行为和短暂性行为相关的大脑异常这些区域的胚胎大脑扩大将得到进一步研究。