Research OverviewResearch in the Jaffrey laboratory is focused on identifying the roles of RNA regulation in neuronal growth, plasticity, and development. RNA regulatory pathways are particularly prominent in neurons. For example, RNA splicing is more highly regulated and is more complex in neurons than in any other cell type. Similarly, RNA editing and trinucleotide repeat-containing mRNA diseases are especially well-characterized in neurons. Another form of RNA regulation that is particularly prominent in neurons is “local” RNA translation, in which mRNA is translated in axons or dendrites, often within spines or axonal growth cones. The human genome also encodes a diverse array of noncoding RNAs, including microRNAs, which are likely to have fundamental roles in neuronal function. Additionally, recent studies have identified new intracellular structures that have roles in regulating the processing of RNAs, including RNA granules, stress granules, and P-bodies. The diversity of these RNA regulatory mechanisms makes it clear that mRNA is not a simple intermediate between DNA and protein, but is regulated by a complex and intricate network of regulatory mechanisms and intracellular structures that have a critical role in gene expression.
Despite the evidence for a widespread and critical role for RNA regulation in neuronal function, surprisingly little is known about the roles of mRNA localization, RNA processing, and noncoding RNAs in neuronal processes. RNA appears to be especially important during the highly dynamic and signaling-intensive processes that occur during the formation and patterning and of the nervous system. We have therefore focused our efforts on understanding the roles of RNA regulation in neurodevelopmental processes such as axonal growth, axonal pathfinding, and synapse formation. These processes are mediated by a variety of extracellular signaling molecules that act on axons and axonal growth cones. We focus on identifying and characterizing novel functions of RNAs in the intracellular signaling pathways that couple receptor activation to the morphological and functional changes in axons and growth cones that characterize these developmental processes.
Our work has resulted in the identification and characterization of several novel modes of signaling that are utilized by axons and growth cones. Axonal growth cones are essentially autonomous signaling outposts since they detect and process signals within a relatively small domain of the cell that is spatially separated from cell bodies by the long and thin axon. One major signaling pathway that we have characterized is local protein translation in axonal growth cones. During embryonic development, when axons are growing toward their targets, axons contain ribosomes, mRNAs, and various components of the translational apparatus. Our laboratory identified the first axonal mRNA that is required for signaling by axonal pathfinding molecules. We have also identified other axonally localized mRNAs that have critical roles in axonal growth. We have generated cDNA libraries from axonal growth cones and made the surprising finding that axons contain mRNAs that encode transcription factors. These findings have fundamentally altered current views of signaling in axons and the mechanisms by which signaling molecules affect growth cones, axons, and cellular function.
We are continuing to explore the roles of axonal mRNAs in processes such as synaptogenesis, axonal branching, and retrograde signaling from axonal growth cones to the cell body. We are also exploring the roles of small RNAs, such as microRNAs in neuronal function, as well their local roles as regulators of axonal mRNA translation. Other areas of interest involve understanding the biological significance of local mRNA degradation in axons, as well as the role of protein ubiquitination and protein processing in axons.
Many of the signaling pathways that we study have roles in neurodevelopmental and other diseases. We are exploring links between axonal signaling pathways and axonal RNAs and autism, mental retardation, and epilepsy. We also have a major interest in designing new RNA-based viral therapies for the treatment of axonal injuries such as spinal cord injury.
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