Elucidating the Molecular Mechanisms of gamma-Protocadherin Localization, Adhesion, and Biochemical Signaling: Implications for Synaptogenesis

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The 22 proteins encoded by the γ-Protocadherin gene cluster (Pcdh-γ’s) belong to the cadherin protein superfamily, a large group of cell adhesion molecules. Deletion of the entire Pcdh-γ gene locus in mice leads to massive neuronal defects and death of animals within hours after birth. Despite an obviously important role for these proteins for CNS development, their mode of action at the cellular and biochemical levels is still poorly understood. Essential questions such as -- Do Pcdh-γ’s mediate cell adhesion or do they rather act as cellular receptors? How are Pcdh-γ’s integrated into the cellular protein interaction network? Which protein motifs are responsible for specific localization and trafficking of individual Pcdh-γ’s in cells? How important is the diversity of Pcdh-γ’s for their function(s)? -- remain unanswered. My proposed projects aim to answer these questions. These projects include identification of the interaction partners of selected Pcdh-γ’s, characterization of the proposed adhesive properties of Pcdh-γ’s and their localization within cells, and as elucidation of the role of posttranslational modifications, such as tyrosine phosphorylation, of Pcdh-γ isoforms. Together, these projects promise to provide the first comprehensive understanding of the mechanisms by which the Pcdh- γ’s control important processes in CNS development such as synapse formation and neuronal survival.