Social Interaction Defects in DV1l Mutant Mice

DV1l 突变小鼠的社交互动缺陷

• 批准号: 6777844
• 负责人: ANTHONY J. WYNSHAW-BORIS
• 金额: $ 13.68万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-06-01 至 2006-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6777844
• 关键词: alleles; amygdala; artificial chromosomes; behavioral /social science research tag; behavioral genetics; biological signal transduction; ethology; gene environment interaction; gene expression; gene interaction; gene mutation; genetic mapping; genetic models; genetically modified animals; laboratory mouse; molecular cloning; neuroanatomy; protein sequence; site directed mutagenesis; social behavior; suppressor mutations

DESCRIPTION (provided by applicant): Social interaction is a fundamental characteristic of most eukaryotic organisms, and it is modulated by both genetic and environmental factors. Social interaction has been productively studied in several animal model systems, leading to the identification of brain regions and neural systems important for this behavior, such as the amygdala and associated structures. However, the genetic contribution to social behavior is currently not well understood. The mouse has been used to define specific genes important for a variety of behaviors. We feel that the mouse can be used as an important model to study the genetics of social interaction for two reasons: it is easy to manipulate mice genetically; and mice display a wide repertoire of social behaviors. In the course of investigating the normal in vivo role of Dishevelled-1 (Dvl1), one of three murine Dvl genes, we discovered that Dvl1-deficient mice exhibit reduced social interaction (Lijam et al. 1997). We recently found that these mice have abnormalities in the amygdala, a brain region known to participate in social behaviors. Thus, Dvl1 mutant mice provide an entry point into pathways important for mammalian social behavior. Dvl1 is a component of the Wnt/Wg pathway that is essential for cell fate determination and proliferation in all multicellular eukaryotic organisms. In addition, Dishevelled from Drosophila positively regulates the planar cell polarity (PCP) pathway. In Drosophila and Xenopus, it is known that distinct domains of Dvl proteins are important for distinguishing between Wnt/Wg and PCP signaling, suggesting that similar mutational analysis can define Dvl functions in mammals. An important outstanding question regarding these mice is: what pathways are mediated through Dvl1 that regulate social behavior? We propose to use the Dvl1-deficient mice to determine the genetic pathways and genes that interact to modify social behavior, and to investigate in detail the effects of these genes on social behavior as well as brain structure and function. Our specific aims are: 1) determine the spatial/temporal expression pattern of the Dvl1 protein required for normal social behavior by using a Dvl1 conditional knockout mouse and relevant Cre lines; 2) determine the domains of the Dvl1 protein required for normal social behavior by producing an allele series of Dvl1 mutants in Dvl1 -/- mice using a novel BAC transgenic strategy; 3) search for suppressors of the Dvl1 -/- social interaction phenotype by performing ENU mutagenesis on Dvl1-/- mice (sensitized screen); and 4) determine regional brain structural and functional defects of mutants produced in Aims 1-3 compared with Dvl1-/- mutants as well as other Dvl mutants.

描述（由申请人提供）：社会互动是大多数真核生物的基本特征，并且受遗传和环境因素的调节。社会互动已经在几个动物模型系统中有效地研究了，从而鉴定了对这种行为重要的大脑区域和神经系统，例如杏仁核和相关结构。但是，目前对社会行为的遗传贡献尚不清楚。该小鼠已被用来定义对多种行为重要的特定基因。我们认为，小鼠可以用作研究社会相互作用的遗传学的重要模型，原因有两个：很容易通过遗传操纵小鼠；小鼠展示了社会行为的广泛曲目。在研究DISEVELLED-1（DVL1）的正常体内作用（三个鼠DVL基因之一）的过程中，我们发现DVL1缺陷型小鼠的社会相互作用降低（Lijam等，1997）。 我们最近发现，这些小鼠在杏仁核中有异常，这是一个已知参与社会行为的大脑区域。因此，DVL1突变小鼠为哺乳动物社会行为重要的途径提供了一个切入点。 DVL1是Wnt/WG途径的一个组成部分，它对于所有多细胞真核生物生物的细胞命运确定和增殖至关重要。此外，从果蝇中脱颖而出可正调节平面细胞极性（PCP）途径。在果蝇和爪蟾中，众所周知，DVL蛋白的不同结构域对于区分Wnt/WG和PCP信号很重要，这表明相似的突变分析可以定义哺乳动物中的DVL功能。关于这些小鼠的一个重要问题是：通过调节社会行为的DVL1介导了哪些途径？我们建议使用DVL1缺陷型小鼠来确定相互作用以改变社会行为的遗传途径和基因，并详细研究这些基因对社会行为以及大脑结构和功能的影响。我们的具体目的是：1）通过使用DVL1条件基因敲除小鼠和相关的CRE线，确定正常社会行为所需的DVL1蛋白的空间/时间表达模式； 2）通过使用新型的BAC转基因策略在DVL1 - / - 小鼠中产生一系列DVL1突变体，确定正常社会行为所需的DVL1蛋白的结构域； 3）通过在DVL1 - / - 小鼠上执行ENU诱变（致敏屏幕）来搜索DVL1 - / - 社会相互作用表型的抑制器； 4）与DVL1 - / - 突变体以及其他DVL突变体相比，确定目标1-3中产生的突变体的区域脑结构和功能缺陷。