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

项目摘要/摘要 社会互动是所有动物物种的基本行为，但 社会性神经回路的形成及其形成的细胞和分子机制很差。 明白了。已有假说认为，大脑发育异常可能会导致脑功能长期改变。 成年后可能表现为行为障碍的大脑回路。与这一想法一致，一个意义重大的 自闭症谱系障碍(ASD)的亚组(约25%-30%)与短暂但显著的 在生命的最初几年，大脑的大小会导致不正常的社交和其他行为。为了进一步支持这一点 假设，我们发现蓬乱的Dvl1-/-；Dvl3+/-突变小鼠显示神经前体细胞增加 一种新的β-连环蛋白/Brn2转录调控失调在胚胎发育过程中的增殖 级联与成人社交/重复行为和大脑异常有关(Belinson等人。2016)。 我们假设β-连环蛋白/Brn2转录级联调控鼻咽癌的增殖和 小鼠大脑发育过程中的分化，导致正常的社会行为。对这一点的失调 级联导致胚胎发育过程中异常的神经发生导致异常的社会行为，这 选择性地破坏成人的大脑结构/功能。我们建议通过以下方法在小鼠身上解决这一假设 采用其他DVL和Brn2遗传小鼠模型，全面的行为分析，以及 最先进的老鼠成像研究，有以下三个目的。 目标1.确定DVL下游的哪些路径负责社会/重复 行为和一过性胚胎脑增大表型。β-连锁素的参与 在胚胎脑增大、社会/重复行为和成人中涉及典型的Wnt通路 大脑结构/功能。为了正式证明这一点，我们将使用一系列带有荧光标记的BAC等位基因 从遗传学角度确定DVL基因在胚胎脑增大、社会性/重复性中的作用 行为和成人的大脑结构/功能在体内是通过规范和/或非规范的Wnt途径进行的。 目的2.确定β-连环蛋白/Brn2转录级联的空间/时间需求 适用于成人社交/重复行为和短暂的胚胎大脑增大。我们将使用条件 Dvl2和Brn2的等位基因以及大脑特异的CRE基因决定空间/时间 β-连环蛋白/Brn2转录级联在胚胎脑增大、社会性/重复性中的需求 行为和成人大脑结构/功能。 目标3.确定与胚胎大脑发育有关的新生儿、断奶和成年大脑区域 和社交/重复行为。磁共振成像(MRI)和扩散张量成像(DTI)研究 在AIMS 1和AIMS 2中研究的小鼠的成年大脑将用于确定新生儿(P0)、断奶(3周大) 和10-12周的成人)与社交/重复行为和短暂性脑异常有关 胚胎脑部增大。将对这些地区进行进一步调查。

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.