Current Research Description

The research goals of my laboratory are to define the roles of primary cilia in cellular function and disease pathogenesis. Primary cilia are typically solitary, immotile appendages present on nearly every mammalian cell type. Primary cilia provide specialized sensory and signaling functions that are essential for normal development and cellular homeostasis. Disruption of ciliary structure or function causes a number of human diseases, collectively termed ciliopathies. Yet, the precise function of most primary cilia and how they contribute to disease pathogenesis is largely unknown. This is especially true for primary cilia on neurons throughout the mammalian brain. Most, if not all, neurons possess a primary cilium upon which certain G protein-coupled receptors (GPCRs) are specifically targeted, suggesting neuronal cilia sense neuromodulators in the extracellular space and provide specialized signaling. The importance of neuronal cilia is highlighted by the fact that ciliopathies are associated with numerous neurological defects, including obesity, cognitive and social deficits, behavioral disturbances, and brain malformations. However, the roles of neuronal cilia in GPCR signaling and how they impact neuronal function are unknown.

We have discovered that the proteins associated with the human ciliopathy Bardet-Biedl syndrome (BBS) are required for proper trafficking of GPCRs into and out of neuronal cilia, suggesting disrupted ciliary GPCR trafficking is the basis for the neurological defects in BBS. We hypothesize that trafficking of ciliary GPCRs coordinates receptor signaling and disruption of ciliary trafficking alters the regulation of GPCR signaling and leads to physiological and behavioral abnormalities. Our goals are to define the mechanisms of ciliary GPCR trafficking, determine the effects of disrupted ciliary GPCR trafficking on signal transduction pathways, and determine the behavioral and physiological consequences. We have developed a unique set of resources for these studies, including; identification of novel ciliary GPCRs/signaling pathways, mouse models of disrupted ciliary GPCR trafficking that impact these pathways, and in vitro tools and systems for defining the mechanisms of ciliary GPCR trafficking and its impact on signaling. These resources will be used synergistically to understand the biology of cilia and ciliopathies.