Rodal to Receive NIH New Innovator Award

The NIH recently announced that Assistant Professor of Biology Avital Rodal will be a recipient of the 2012 NIH Directors New Innovator Award. The award allows new, exceptionally creative and ambitious investigators to begin high impact research projects. Granted to early stage investigators, candidates are eligible for the award for up to ten years after the completion of their PhD or MD. The award emphasizes bold, new approaches, which have the potential to spur large scientific steps forward. This year’s award was made to fifty-one researchers, and provides each with 1.5 million dollars of direct research funding over five years.

The Rodal lab studies the mechanisms of membrane deformation and endosomal traffic in neurons as they relate to growth signaling and disease. Membrane deformation by a core set of conserved protein complexes leads to the creation of tubules and vesicles from the plasma membrane and internal compartments. Endocytic vesicles contain, among other cargoes, activated growth factors and receptors, which traffic to the neuronal cell body to drive transcriptional responses (see movie). These growth cues somehow coordinate with neuronal activity to dramatically alter the morphology of the neuron, and disruptions to both endocytic pathways and neuronal activity have been implicated in neurodegenerative diseases such as amyotrophic lateral sclerosis and Alzheimer’s disease.

Dr. Rodal hopes to determine how neuronal activity affects the in vivo function and biochemical composition of the membrane trafficking machinery, by examining the transport of fluorescently labeled growth factor receptors in chronically or acutely activated neurons at the Drosophila neuromuscular junction (NMJ). Her group will combine these live imaging studies with a proteomic analysis of endocytic machinery purified from hyper-activated and under-activated neurons. By investigating the interplay between neuronal activity, membrane deformation, and receptor localization in live animal NMJs, she hopes to gain a better understanding of the strategies that healthy neurons employ to regulate membrane trafficking events, and provide new insight into specific points of failure in neurodegenerative disease.

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Signals on the move

A hallmark feature of eukaryotic cells is their intricate subcellular membrane compartmentalization, which biochemically and spatially isolates cellular processes including signal transduction, protein synthesis, and energy production. Membrane-spanning proteins such as growth factor receptors are transported through these compartments by the actions of a host of membrane binding proteins that bend, pinch and move bits of cargo-containing membrane from one compartment to another. Growth factor receptors change their signaling properties as they transit through these different compartments, and so cells can turn growth factor signaling up or down by regulating the rate of transit. The challenge is to understand how networks of hundreds of interacting membrane deforming proteins work to control cargo traffic, and how these proteins might themselves be regulated by the cell to reroute cargo.

Live imaging of dynamic interactions between subcellular compartments in fly neurons.
(click to watch movie)

Now, in a recent study published in the Journal of Cell Biology, new Biology faculty member Avital Rodal, together with Troy Littleton at MIT, identify a novel interaction between two membrane-binding proteins, Nervous Wreck (Nwk) and Sorting Nexin 16 (SNX16), that are critical for controlling the traffic of growth factor receptors that drive the expansion of neuronal arbors. Using the neurons that innervate muscles in fruit fly larvae as a model, Rodal and colleagues show that a physical association between these two proteins is necessary to turn off signaling by receptors that have been previously activated by growth factors. Perplexingly, though Nwk and SNX16 must physically interact to execute their role in driving membrane movements, they appear to reside in different subcellular compartments, in different locations within the neuron. To solve this conundrum, Rodal and colleagues took advantage of the spinning disk confocal microscope in the Brandeis Correlative Light and Electron Microscopy facility to look at the dynamic behavior of these compartments in living neurons in larvae. They found that the two distinct compartments inhabited by Nwk and SNX16 undergo dynamic and transient interactions, which represent the point in space and time that signaling receptor cargo is transferred between compartments. These receptor trafficking events are implicated in diseases ranging from neurodegenerative disease to mental retardation and addiction, underlining the health importance of understanding how signal transduction is modulated by intracellular membrane traffic in neurons.