Firing by remote control

Kosik has continued to profile neuronal miRNAs to identify those potentially involved in neuronal plasticity, the original motivation for this work.

"One of the current interests in the field is to determine and understand the functions that are unique to dendrites," he says. "The ongoing issue of mRNA distribution between dendrites and the cell body also applies to the miRNAs."

To address this, Kosik's group combined their miRNA profiling with a laser-capture technique to look at specific cells or parts of cells. "We were able to quantify miRNAs in the dendrite and cell body compartments separately by laser capturing just the dendrites or just the cell bodies and profiling the contained set of microRNAs."

Most neuronal miRNAs were distributed throughout the neuron. However, as is the case with mRNAs, a subset of miRNAs were either relatively enriched or depleted out in the dendrites.

"We then had a repertoire of miRNAs that are probably involved in regulating protein translation locally, due to their specific and restricted location near the synapse. We also had supremely good candidates for targeting miRNAs involved in plasticity."

Home delivery system

For those involved in RNA research there is a great deal of interest in not just what miRNAs are doing in dendrites but how they get there, he says.

A number of years ago, his group reported structures in neurons they called RNA granules. Kosik describes this granule as like a translocation vehicle, carrying RNA molecules to their required destinations nearer the synapse when needed to regulate local translation.

In further studies, Kosik's team found these RNA granules to be devoid of transfer RNA and other elements of the translation system needed to turn mRNA into proteins. It seemed then that this intracellular compartment is not merely a delivery system, but also acts as a holding unit for mRNA.

On stimulation, the contents would presumably be released for an efficient synaptic response (sort of like home delivery instead of take-away).

Recent evidence suggests another type of intracellular compartment that holds RNA called the P body or processing body.

"We are really excited right now to know how the RNA granules, which contain certain categories of mRNAs, are getting to their destinations, and then how these P bodies, which are perhaps involved in actual storage of mRNAs or maybe even their degradation, are talking to the granules. How are these different subcellular units dynamically related?"

And now of course, the same issue applies to miRNAs. "The real challenge for neurons is to get everything they need to the right place when they need it, including miRNAs."

One possibility is that the processed mature miRNA hitches a ride on a target mRNA containing dendritic localisation signals. "Alternatively, dendritic miRNAs might be processed locally from precursor molecules, in which case the cell must also move the miRNA biogenesis machinery out there. This is going to be a really exciting direction in the field."

Kosik's research now covers many topics, including the more recent and exciting work on miRNAs in the nervous system. "I like to think my research encompasses a common theme - that we are really talking about problems of synaptic plasticity with all the various issues I research.

"With Alzheimer's disease it is the loss of plasticity and how you can help people who are losing their synaptic efficacy, and miRNAs will definitely be important there. In fact, recent work has shown particular miRNAs targeting the amyloid precursor protein, so they may soon become directly relevant in that field also.

"So, my ideal for the lab would be to work towards making all these connections even stronger and eventually link up, but if we don't and all we do is get insights into synaptic plasticity I would be very happy."