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Do you think you are more complex than yeast? Most people would probably say so, especially if they compared our trillions of cells with yeast, which are made up of single cells.

But if one were to judge complexity only by the number of protein-producing genes in each organism, humans wouldn't seem quite so advanced — each yeast cell contains about 6,000 genes, while we humans have just about five times as many, around 30,000.

Where does our complexity lie, then, if not with the number of genes in our genome?

One hypothesis gaining ground, among others, involves tiny 22-base long pieces of RNA called microRNAs. Proponents say these mini-molecules — which are transcribed from "junk" DNA between protein-encoding genes — may be working with proteins, DNA, and other RNA molecules to create a diverse array of skin, muscle, and brain cells from that seemingly small set of 30,000 genes.

Bolstering that theory, Columbia University Medical Center researchers have now found the first microRNA that operates in the brain, according to a study by Dr. Oliver Hobert, assistant professor of biochemistry & molecular biophysics in the Center for Neurobiology and Behavior, and Graduate School of Arts and Sciences student Robert Johnston. The work was published in the Dec. 18/25 issue of Nature.

The newly discovered microRNA helps make the left side of the brain in the C. elegans worm different from the right. "Our brain, and that of the worm, only appear bilaterally symmetrical," Dr. Hobert says, with the left hemisphere looking like a mirror image of the right. "But the left does things differently from the right, and neuroscientists don't understand how that happens."

In C. elegans, much of the brain's lopsidedness is due to the worm's need for a strong sense of taste. With no eyes or ears, wild worms rely on chemical cues to find food and potential mates as they wiggle through the dirt. To increase the acuity of the sense of taste, sensory neurons, which usually come in symmetric left-right pairs, are endowed with different receptors so the left one is able to taste different things from the right one.

At first, the left and right taste neurons develop the same way. Then, expression of the microRNA, called lsy-6, on the left side of the brain turns the left neuron into a distinctly different cell, the researchers found. As a result, two taste receptors are expressed in the left neuron, while a third, different receptor is expressed in the right.

"One important thing we've shown is that microRNA is used to create neuronal diversity. People usually say cellular diversity can be created from a limited number of proteins when the proteins are used in different combinations," Dr. Hobert says. "And that's probably partly true. We're showing that it's not just different combinations of proteins that create complexity, but microRNA as well."

Overall, a few hundred microRNAs have been identified since the first was found in 1993 in C. elegans, including 150 or so in humans. Whether they're enhancing the power of our genes to a large degree is still uncertain: The functions of most are unknown. In the past year, though, reports have tied microRNAs to plant development, cell death, and, now, brain development.

Also, many more microRNAs may exist. Most of the known microRNAs — although not lsy-6 — were detected by a computer search of the entire genome. "That ours wasn't identified by a computer shows the search was not complete," Dr. Hobert says. "It may mean 10,000 more may exist, or two more may exist. It should get people looking for more because we are just beginning to appreciate how important microRNAs are."

Research was supported by the NSF and the NIH.

–Susan Conova


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