Vivian Budnik, PhD
Department of Neurobiology
University of Massachusetts Medical School
Synaptic Communication Goes Viral
One of the central questions for neurobiology is how synapses are able to modulate the strength and location of their connections in response to stimuli. This phenomenon allows for synaptic plasticity in learning and sensory processing. Vivian Budnik is interested in the mechanisms of synaptic signaling, which may allow cells to communicate with each other and provoke plastic responses. Extracellular vesicles (EVs) are one such possible explanation Doctor Budnik poses for how trans-cellular communication can happen, via the transport of integral membrane proteins, non-diffusible signals, and even possibly neurotoxic prion-like proteins.
Initially, Doctor Budnik was interested in the way that synapses are formed. Using the Drosophila neuromuscular junction as a model, she observed that Wingless – a critical signaling molecule for synapse development – is released from the neuron to communicate with the postsynaptic muscle. She identified Evenness Interrupted (Evi) as being responsible for this release of Wingless. She then sought to determine how, mechanistically, Evi exerts control over Wingless release by first looking at larvae expressing neuronally-driven Evi-GFP to see where Evi resides. She observed Evi not only presynaptically, but also in small postsynaptic puncta. Thus, it appeared that Evi is trafficked into neuronally-derived EVs, and that it might affect Wingless’ ability to incorporate into these EVs. In fact, Doctor Budnik’s lab had been observing multi-vesicular bodies – the precursors of EVs – at synaptic terminals by electron microscopy since the 90s but had always ignored them for lack of understanding what they might be there for. Doctor Budnik then conducted a screen to identify factors that could prevent release of these Evi-positive EVs and she identified Rab11, a critical regulator of the endosomal pathway. In the absence of Rab11, EV release is abolished.
Upon setting out to identify other EV cargoes, Doctor Budnik found mRNA encoding dARC, a protein that is considered the “master of synaptic plasticity” and that is enriched in EV’s. Furthermore, she found that there is a region of the dARC mRNA that is similar to a region of viral DNA, and found that the dARC protein is actually capable of associating with its own mRNA to form a “capsid”-like structure, suggesting that EVs may be able to transmit genetic material between cells in a way that is very similar to the way viruses transmit.
Doctor Budnik’s visit highlighted her impressive contributions to the fields of cellular biology and neuroscience by shedding light on the molecular mechanisms guiding EV formation as well as providing insight into the different purposes that these EVs may be able to serve in trans-cellular communication.