John Gerard Flanagan
Our broad interest is to understand how cell-cell signaling molecules set up spatial pattern, particularly in the formation of neuronal connections. We use a range of approaches including biochemical and cell biological studies, high-throughput analysis of protein-RNA interaction networks, and in vivo mammalian models.
Wiring up the nervous system: molecular cues for axon guidance and regeneration. The functioning of the nervous system depends on the precise and complex spatial order of its connections. Our work identified some of the first known axon guidance cues that initially set up this pattern of connections during development. Currently we are particularly interested in mechanisms to promote regeneration and repair of axonal connections in the adult. When connections in the adult central nervous system are lost due to injury or disease, regeneration is minimal, creating a major clinical challenge. This is due at least in part to the presence of endogenous inhibitors in the CNS. Our work identified a receptor for a major class of these inhibitors, the chondroitin sulfate proteoglycans. Identification of this receptor-ligand interaction now provides opportunities to study the basic biology as well as novel therapeutic approaches. We are also studying mechanisms of neurodegenerative disease.
RNA-based mechanisms in axon guidance.
Regulation of RNA translation provides a way to target protein synthesis to specific locations within the cell. The neuron, being a highly asymmetric cell, provides an especially good model to study this, and we and others have shown that protein synthesis can be highly localized within the neuron, and plays functional roles in axon guidance and synapse plasticity. In recent studies we have found that cell surface receptors associate with protein synthesis machinery, providing a generalizable way for cells to localize and regulate translation, based on a transmembrane translation regulation complex. We are continuing to study RNA-based mechanisms, including high-throughput and computational analysis of protein-RNA interaction networks, and studies of functional roles for these mechanisms in axon growth and guidance.
Building C2, Room 523
240 Longwood Avenue
Boston, MA 02115