Sci. Aging Knowl. Environ., 24 March 2004
The Little RNAs That Could
Midget RNA molecules trigger neuron maturation through unexpected mechanism
Like many teenagers, stem cells won't grow up without a push. New research reveals that RNA snippets provide a shove, inciting brain stem cells to mature. The work suggests that RNAs instigate the process by changing a gene-blocking protein into a gene activator. The study is the first to show that the miniature molecules can turn genes on as well as off.
Stem cells that dwell in the adult brain can become neurons or other cell types. Would-be neurons crank up genes that orchestrate their maturation. However, researchers don't know what flips these genes on. In the last decade, molecular biologists have discovered that tiny RNA molecules help govern gene output. They stifle protein production by glomming onto messenger RNA in the cell's cytoplasm. Researchers are keen to know whether small RNAs also activate genes. Neuroscientist Fred Gage of the Salk Institute in La Jolla, California, and colleagues wanted to find out whether these molecules play a role in neuron specialization.
The team isolated stem cells from the hippocampus and netted minuscule RNA molecules. One variety--which the researchers called a small modulatory RNA (smRNA)--stood out because 64 genes that turn on during neuron maturation carry a matching sequence. A "master regulator" protein called NRSF/REST latches onto these genes, shackling them in non-neurons. By adding the tagged RNA to a mixture of cell contents, the researchers showed that it adheres to NRSF/REST. To determine whether the smRNA triggers the maturation genes, they engineered cells to destroy it. Control cells began to morph into neurons, but altered cells remained immature, suggesting that the tiny RNA activates genes that drive maturation. The molecule might work by preventing NRSF/REST from attaching to the DNA, the researchers hypothesized. However, further experiments showed that the smRNA didn't evict NRSF/REST but somehow converted the protein from a gene blocker into a gene activator. The researchers aren't sure how the transformation occurs or what prods the cell to manufacture the smRNAs.
The finding adds "a new role for noncoding RNAs in influencing cell function," says neuroscientist Jack Parent of the University of Michigan, Ann Arbor. Previous work revealed that small RNAs operate in the cytoplasm and turn protein production off, but "nobody had been able to show that these [molecules] act on gene activity in the nucleus." The results mesh with a growing realization among stem cell experts, says neuroscientist Evan Snyder of the Burnham Institute in La Jolla, California. Researchers have sought a few "stemness" genes that dictate what a cell becomes. By revealing a new type of regulation, he says, the work backs the idea that the decision depends on more than just the activity of a handful of genes. He adds that the nervous system needs involved mechanisms to control maturation, because it "has to have exactly the right number of neurons in exactly the right place making exactly the right connections." Further studies might reveal how smRNAs help stem cells grow up into well-adjusted, well-connected adults.
March 24, 2004
Science of Aging Knowledge Environment. ISSN 1539-6150