Tyrosine Kinase Pathways That Control Axon Guidance

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The synapse is the fundamental unit of the nervous system. Failure in synaptic development and/or function appears to underlie a wide variety of human neurological disorders from epilepsy and schizophrenia to congenital mental retardation. Fragile X Syndrome is the most common cause of hereditary mental retardation, and has been linked to defects in synapse morphogenesis through the FMR locus which encodes an RNA-binding protein that controls protein synthesis, likely via a microRNA-dependent mechanism. However, the neuronal targets that FMR controls, and the pathways that regulate FMR activity in space and time are poorly understood. Drosophila has recently emerged as an exciting model system to study the role of FMR (dfmr1) in synaptogenesis. Work from the initial funding period of this grant suggests that dfmrl acts in collaboration with the Abelson (Abl) tyrosine kinase to restrict synapse size. Additional work from our lab suggests that the LAR receptor tyrosine phosphatase acts upstream to antagonize Abl and dfmrl to promote synapse growth, implicating the coordination of cytoskeletal remodeling and translational control, and a link between dfmr1 and extracellular signals. Our identification of two low-nanomolar LAR ligands that have opposite effects on synapse growth extends this hypothesis, raising the possibility that competing signals fine-tune synapse morphogenesis or stabilization upstream of the Abl kinase. During the next funding period, we will determine the order of gene activities in this pathway, define the link between Abl and dfmr1 activity, and determine whether dfmr1 acts via miroRNAs to regulate key synaptic targets.