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

• 批准号: 10191047
• 负责人: ANTHONY J. WYNSHAW-BORIS
• 金额: $ 45.61万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-11 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10191047
• 关键词: Address; Adult; Affect; Age; Alleles; Animals; Bacterial Artificial Chromosomes; Behavior; Behavior Disorders; Behavioral; Brain; Brain region; Cell Differentiation process; 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; 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; behavioral phenotyping; beta catenin; brain abnormalities; brain circuitry; brain overgrowth; brain size; cognitive process; fetal; frontal lobe; human model; 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; stem cell proliferation

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.

项目总结/摘要 社会互动是所有动物物种的基本行为，但社会互动的发展时间是一个重要的因素。 社会神经回路的形成和控制其形成的细胞和分子机制很差， 明白据推测，异常的大脑发育会导致长期的改变， 大脑回路可能会在成年后表现出行为障碍。与此相一致，一个重要的 自闭症谱系障碍（ASD）的一个子集（约25-30%）与短暂但显著的增加有关， 在生命的最初几年，大脑的大小，导致异常的社交及其他行为。为了进一步支持这一点， 假设，我们发现Dishevelled Dvl 1-/-; Dvl 3 +/-突变小鼠显示出增加的神经祖细胞 (NPC)通过一种新的β-catenin/BRN 2转录调节异常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反应（Belinson等人，2016）。 我们假设β-catenin/BRN 2转录级联调节NPC增殖， 在小鼠大脑发育过程中的分化，导致正常的社会行为。这种失调 级联反应导致胚胎发育过程中异常神经发生引起的异常社会行为， 选择性地破坏成人大脑结构/功能。我们建议在小鼠中解决这一假设， 采用额外的Dvl和Brn 2遗传小鼠模型，全面的行为分析，和 本领域的小鼠成像研究，在以下三个目标。 目标1.确定Dvl下游的哪些途径负责社交/重复 行为和短暂的胚胎脑增大表型。β-catenin的参与 暗示了典型的Wnt通路在胚胎脑增大，社会/重复行为，和成年 大脑结构/功能为了正式证明这一点，我们将使用一系列荧光标记的BAC等位基因 为了从遗传学上确定Dvl基因在胚胎脑增大、社会/重复性发育中的作用， 行为和成人脑结构/功能是通过体内的经典和/或非经典Wnt途径。 目标2.确定β-catenin/BRN 2转录级联的空间/时间要求 成年人的社会/重复行为和短暂的胚胎脑扩大。我们将使用条件 Dv 12和Brn 2的等位基因以及脑特异性克雷斯，以遗传地确定空间/时间 β-catenin/BRN 2转录级联在胚胎脑增大中的需求，社会/重复 行为和成人大脑结构/功能。 目标3.确定与胚胎大脑生长有关的新生儿，断奶和成年大脑区域 社交/重复行为。磁共振成像（MRI）和扩散张量成像（DTI）研究 目的1和2中研究的成年小鼠脑的50%将用于确定新生（P0）、断奶（3周龄） 和10-12周龄的成年人）与社会/重复行为和短暂性 胚胎脑增大这些地区将进一步调查。