Social Interaction Defects in DV1l Mutant Mice

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，它受到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进行了富有成效的研究，导致识别对这种行为重要的大脑区域和神经系统，如杏仁核和相关结构。然而，基因对社会行为的影响目前还没有得到很好的理解。老鼠已经被用来确定对各种行为重要的特定基因。我们认为，小鼠可以作为研究社会互动遗传学的重要模型，有两个原因：易于对小鼠进行遗传操作；老鼠表现出广泛的社会行为。在研究三种小鼠Dvl基因之一的disheveled -1 （Dvl1）在体内正常作用的过程中，我们发现，缺乏Dvl1的小鼠表现出社交互动减少（Lijam et al. 1997）。我们最近发现这些老鼠的杏仁核有异常，杏仁核是参与社会行为的大脑区域。因此，Dvl1突变小鼠为研究哺乳动物社会行为的重要途径提供了一个切入点。Dvl1是Wnt/Wg通路的一个组成部分，在所有多细胞真核生物中，Wnt/Wg通路对细胞命运决定和增殖至关重要。此外，来自果蝇的disheveled正调控平面细胞极性（PCP）通路。在果蝇和非洲爪蟾中，已知Dvl蛋白的不同结构域对于区分Wnt/Wg和PCP信号非常重要，这表明类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的突出问题是：通过Dvl1介导的调节社会行为的途径是什么？我们建议使用dvl1缺陷小鼠来确定相互作用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。我们的具体目标是：1)通过使用Dvl1条件敲除小鼠和相关Cre系，确定正常社会行为所需的Dvl1蛋白的时空表达模式；2)利用一种新的BAC转基因策略，在Dvl1 -/-小鼠中产生一系列Dvl1突变等位基因，确定正常社会行为所需的Dvl1蛋白结构域；3)通过对Dvl1-/-小鼠进行ENU诱变（致敏筛选），寻找Dvl1-/-社会互动表型的抑制因子；4)比较Aims 1-3中产生的突变体与Dvl1-/-突变体以及其他Dvl突变体的脑区域结构和功能缺陷。

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.