Neurons are consummate multi-taskers. They respond to and memorise a barrage of signals by making subtle changes at individual synapses and basically learn from experience.

This ability, which enables the nervous system to learn and to retain memories, is referred to as neuronal or synaptic plasticity.

The changes may be macroscopic or occur at the molecular and physiological level. Some forms of plasticity at the level of an individual synapse rely on the neuronal cellular machinery making protein available quickly and in the right amounts.

According to Professor Kenneth Kosik of the University of California Santa Barbara, who visited Australia this year to address the 7th Discovery Science and Biotechnology meeting, this requirement seems particularly well suited to a microRNA-regulated system of local regulation.

MicroRNAs (miRNAs), discovered just over a decade ago, revealed a completely new and unsuspected level of gene regulation.

These non-coding RNA molecules regulate gene expression post-transcriptionally via RNA silencing. Similar to the inhibitory RNA (RNAi) system, the 21-nucleotide miRNAs bind to complementary regions in target mRNAs to regulate translation via mRNA degradation or translational repression.

First identified in C. elegans, we now know that miRNAs are expressed widely in metazoan cells, with the potential to modulate around one-third of coding mRNA expression in mammals.

In the nervous system, miRNAs have key roles in development, and possibly in mature neurons as mediators of plasticity. Around 500 human miRNA sequences are known, although their mRNA targets, and therefore, their functional roles in specific cells remain largely a mystery.

Historical perspective

Kosik has been interested for a number of years in neuronal plasticity and its impairment in neurodegeneration. More specifically, he wants to know how translation is regulated at neuronal dendrites, which of course can be a long way from 'central control' in the nucleus.

It is well established that neuronal synapses are subject to individual, very local control, and that this local mechanism involves translational regulation.

Although not involved at the discovery end of the miRNA story, Kosik was quick to realise how these groundbreaking discoveries were extremely relevant to the phenomena of neurons and plasticity.

"It struck me as an elegant way that nature would do the kinds of things that we were interested in," he says.

At that time, there was very little known about miRNAs in the nervous system. So, before deciding on the miRNA species to study in their specific research context, Kosik's group needed to ascertain how many and which miRNAs are present in neurons.

Kosik says he was lucky in this endeavour - a very talented postdoc in his lab at the time, Anna Krivchevsky, devised a method to profile miRNAs. This was one of the first techniques established for profiling many miRNAs in a single experiment, he says.

The method involved making the complementary sequences of known miRNAs into trimers using their antisense sequences. She then put these onto a nylon filter together with RNA purified from brain or brain cultures.

"This technique turned out to be a goldmine for us - particularly for getting started in looking at miRNAs in neurons. There are a lot more advanced ways now to attack the same problems, but her method gave us and other groups an early look at the particular miRNAs that might be important for say neuronal plasticity."

Soon after, Kosik's group established that miRNAs are turned on during synaptogenesis and that some are found in neuronal compartments called polysomes - these are the actively translating pools of mRNAs.

"From there, we started profiling everything we could get our hands on - neurons of course, but also tumours and stem cells." Kosik's group soon identified an miRNA called mir21 that was extremely elevated in glioblastomas and also seemed to work in apoptosis suppression pathways, one of the critical ways in which cancer progresses.

It turned out that mir21 is markedly upregulated in many tumour types, and is now recognised as perhaps the most commonly disregulated miRNA in cancer. Work on this project remains ongoing in Kosik's lab in addition to work in the nervous system, particularly on the role of mir21 in apoptosis more generally.

Although some neurological diseases have now been linked to miRNAs, most interest is still in the field of cancer biology. The term oncomirs was even coined to describe cancer-related miRNAs like mir21.