Peptides of the Transforming Growth Factor-IS/Bone Morphogenetic Protein (TGF-IS/BMP) family regulate multiple events during development of the nervous system and are key modulators of neuronal function in mammals. Glass bottom boat (Gbb), a Drosophila BMP, and its receptor Wishful thinking (Wit) define a signaling system that regulates synaptic plasticity at the neuromuscular junction (NMJ). Gbb acts as a retrograde signal (from muscle to innervating neuron), and while it is not required for neuron survival, it is essential for proper motoneuron synaptic development and function. Although retrograde signals like Nerve Growth Factor have been known for years, the molecular mechanisms responsible for their subcellular trafficking have been elusive. BMP's are new instances of retrograde signaling in Drosophila, allowing the study of this process in a genetic model organism. Preliminary data suggest that retrograde axonal transport is the mechanism for BMP signal trafficking from the NMJ in the periphery to the neuron nucleus in the CNS. To investigate the translocation of the BMP signal we will develop an optical biosensor that can report BMP pathway activation in vivo. A combination of Bimolecular Fluorescence Complementation, (BiFC), Fluorescence Resonance Energy Transfer (FRET) and live imaging of the fluorescently tagged components of the pathway (ligands, receptors and nucleocytosolic messengers) will follow the traffic of the BMP signal. These studies will be performed in cell lines and in whole animals, and the results will be verified by analysis of tissue-specific mutants of molecular motors. Modulation of synaptic efficacy is an essential process in nervous system function, and target-derived retrograde signals play a key role in this process, including the recently described role of BMPs. The use of genetic tools in combination with high resolution imaging techniques will allow us to generate and validate an optical biosensor that will be of general utility to study BMP pathway activation in live samples. The pathway defined by Wit in the fly nervous system is likely to be at work in regulation of synaptic efficacy in other organisms. Learning the mechanism of BMP signal transport will have a major impact in our understanding of the regulation of synaptic growth and synaptic plasticity. Defects In axonal transport in neurons are critical factors in the pathogenesis of a number of human neurodegenerative disorders, including Alzheimer's and Huntington's diseases. The information we obtain about BMP signal retrograde axonal transport will improve our knowledge of the trafficking of other signals, such as neurotrophins, and of the role of the disregulation of signal traffic in the pathogenesis of human neurodegenerative disease. ? ?
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