Project Summary: Autism is a debilitating neurodevelopmental disorder associated with social and cognitive deficits. Autism compromises the quality of life of affected individuals and place an enormous financial and emotional burden on families and the healthcare system. Advances that promote novel therapeutic approaches are thus a critical need. Mutations in CTNND2, encoding ?-catenin, have been identified in autism. However, the normal functional roles of ?-catenin and how autism mutations perturb this functional role remain unclear. We have identified critical roles for ?-catenin in regulating dendrites, spines and transcription. Based on our preliminary data, we propose that ?-catenin interacts with specific interactors in different cellular compartments to function in these diverse signaling pathways. Further, we propose that autism mutations perturb these interactions or ability to function in these signaling pathways, thus compromising neural circuit formation and contributing to the phenotype of autism. In this proposal, we propose to take advantage of an affinity purification technique to identify and characterize compartment specific binding partners of ?-catenin from the mouse hippocampus. We expect that these studies will aid in further defining the functional roles of ??catenin and delineate the signaling pathways that are aberrant in autism associated with mutations in CTNND2. Thus these studies will eventually aid the development of novel therapeutic approaches for this devastating disorder.