Social Interaction Defects in DV1l Mutant Mice

描述(申请人提供)：社会互动是大多数真核生物的基本特征，它受遗传和环境因素的调节。在几个动物模型系统中对社会互动进行了卓有成效的研究，导致识别出对这种行为重要的大脑区域和神经系统，如杏仁核及其相关结构。然而，基因对社会行为的贡献目前还没有被很好地理解。老鼠已经被用来定义对各种行为重要的特定基因。我们认为，老鼠可以作为研究社会互动遗传学的重要模型，原因有两个：很容易从基因上操纵老鼠；老鼠表现出广泛的社会行为。在研究Dvl1(三个小鼠Dvl基因之一)在体内的正常作用的过程中，我们发现Dvl1基因缺陷的小鼠表现出减少的社会互动(Lijam等人。1997年)。我们最近发现，这些小鼠的杏仁核存在异常，杏仁核是已知的参与社会行为的大脑区域。因此，Dvl1突变小鼠提供了进入哺乳动物社会行为重要途径的切入点。Dvl1是Wnt/Wg途径的一个组成部分，在所有多细胞真核生物中对决定细胞命运和增殖是必不可少的。此外，果蝇的蓬乱对平面细胞极性(PCP)途径有正向调节作用。在果蝇和非洲爪哇中，DVL蛋白的不同结构域对于区分Wnt/Wg和PCP信号是重要的，这表明类似的突变分析可以定义哺乳动物的DVL功能。关于这些小鼠的一个重要的悬而未决的问题是：通过Dvl1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。我们的具体目标是：1)通过使用Dvl1条件基因敲除小鼠和相关的Cre系来确定正常社会行为所需的Dvl1蛋白的时空表达模式；2)通过使用新的BAC转基因策略在Dvl1-/-小鼠中产生一系列Dvl1突变基因来确定正常社会行为所需的Dvl1蛋白的结构域；3)通过对Dvl1-/-小鼠进行ENU突变来寻找Dvl1-/-社会相互作用表型的抑制因子(敏化筛选)；以及4)确定与Dvl1-/-突变体和其他Dvl1突变体相比，目标1-3产生的突变体在脑结构和功能上的区域缺陷。

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.