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.
