The long-term goal of this project is to elucidate signaling mechanisms underlying synapse development and plasticity. Our studies in the previous funding cycle demonstrate that Wnts, pivotal and phylogenetically conserved synaptic organizers, are released via exosomes, extracellular vesicles containing proteins and RNAs, at synaptic boutons of the Drosophila larval neuromuscular junction (NMJ). Our studies also provide evidence that a retrograde signal mediated by Synaptotagmin 4 conveys Wnt signals, and is also controlled by exosome release from presynaptic boutons. These studies place trans-synaptic exosome communication as a key coordinator of pre- and postsynaptic modifications. Cell-cell signaling through exosomes is just beginning to be documented during immunity, the spread of cancer, and intercellular prion transmission in the CNS. In addition, exosomes are emerging as promising vectors for the delivery of targeted therapies. However, most studies of exosomes have been carried out in cell culture, and exosome function in the nervous system is virtually unknown. Our demonstration that exosomes mediate trans-synaptic signaling in vivo, establish Drosophila as a powerful model system to efficiently unravel mechanisms of exosome release and trans-synaptic transfer. Wnt misregulation is associated with a number of cognitive disorders, such as Schizophrenia and Alzheimer's disease. Thus, understanding the mechanisms of Wnt signaling in the nervous system has important implications for the design of clinical strategies to treat these conditions. In this project our experimental strategies will mak extensive use of genetics and state-of the art cellular approaches in vivo, to elucidate the mechanisms of exosome release at synaptic sites and the principles underlying the exosome regulation of synapse development and plasticity. We will (1) identify the molecular machinery mediating exosome release by synaptic boutons, (2) determine the synapse specificity or global nature of retrograde signaling through exosomes, and (3) characterize the role of a Wnt protein in Synaptotagmin 4-mediated retrograde signaling. The outcomes of this project will constitute a significant advancement in our understanding of Wnt signaling at synapses, and promises to accelerate the development of exosomes for targeted therapies.
In humans, misregulation of Wnt signaling is associated with cognitive disorders, such as Schizophrenia, bipolar disorder, and Alzheimer's disease. Therefore, understanding Wnt function is crucial for our ability to design clinical strategies to treat these conditions. We have established that Wnts are released associated with exosomes as a novel communication pathway. Exosomes have been implicated in cancer, immune function, and the spreading of prions as well as Alzheimer's disease lesions, but their function is still largely unknown. Exosomes are also emerging as promising vectors for the delivery of gene targeting therapies. In this proposal we will make extensive use of genetics and sophisticated cell biology methodology to understand exosome release at synapses and their impact on Wnt signaling in the nervous system.
| Ashley, James; Cordy, Benjamin; Lucia, Diandra et al. (2018) Retrovirus-like Gag Protein Arc1 Binds RNA and Traffics across Synaptic Boutons. Cell 172:262-274.e11 |
| Budnik, Vivian; Ruiz-Cañada, Catalina; Wendler, Franz (2016) Extracellular vesicles round off communication in the nervous system. Nat Rev Neurosci 17:160-72 |
| Packard, Mary; Jokhi, Vahbiz; Ding, Baojin et al. (2015) Nucleus to Synapse Nesprin1 Railroad Tracks Direct Synapse Maturation through RNA Localization. Neuron 86:1015-1028 |
