Development of the mouse forebrain is controlled by a complex network of transcriptional regulators that include homeodomain proteins. The DLX2 homeodomain protein is expressed in restricted areas of the developing forebrain, in particular the striatal anlage. The striatum is a forebrain structure that regulates motor functions and is abnormal in many devestating human disorders including Parkinson's and Huntington's diseases. Mutational analysis of the DLX1 and DLX2 genes reveals their essential role in striatal development. To test the hypothesis that functions of the DLX2 protein may be regulated by interaction with other proteins, I used the yeast 2-hybrid system and identified a novel protein (DIP2, for DLX2-interacting protein) that has 4 PDZ domains, one of which interacts with DLX2. The PDZ domains are found in a variety of proteins. They mediate specific protein-protein interactions that integrate signaling pathways in the cell and regulate cell differentiation. Identification of DIP2 as a partner of DLX2 suggests a novel transcriptional regulatory role for PDZ domain proteins. This proposal is aimed at characterizing the functional relationships between DIP2 and DLX2, identifying additional proteins that interact with DIP2 via the PDZ domains, and unveiling the functions of DIP2 in vertebrate brain development.