Brain Gain: Odd RNA converts stem cells into neurons

Like a bicycle messenger carrying blueprints across town, ribonucleic acid, or RNA, typically ferries protein-building instructions across a cell. Scientists exploring how brain cells form have found evidence that RNA does a lot more, however.

They’ve discovered a new kind of RNA that can transform unspecialized rodent brain cells into full-fledged neurons. By binding to a single protein, the RNA turns on dozens of neuron-specific genes, researchers report in the March 19 Cell.

“It’s interesting that a single, small RNA can act as a switch on a protein that regulates a variety of genes,” says study coauthor Fred H. Gage of the Salk Institute in La Jolla, Calif.

While much of the RNA within a cell contains the recipes for proteins, many short RNA strands don’t carry such codes. Some of these noncoding RNAs, called microRNAs, have been implicated in the growth and development of worms, flies, and more-complex animals (SN: 1/12/02, p. 24: Biological Dark Matter).

Gage studies how new nerve cells form, so he and his colleagues looked into whether noncoding RNAs influence unspecialized brain cells, or neural stem cells, isolated from adult rats. Gage’s team used chemicals to coax the cells in laboratory dishes into creating neurons instead of other types of brain cells and then harvested all the RNAs within the new neurons.

One small RNA stood out because it was double stranded. RNA typically is made up of a single strand of building blocks called nucleotides, while DNA consists of two entwined strands of nucleotides.

Further studies revealed that the double-stranded RNA latches on to a protein that itself binds DNA. This protein, dubbed NRSF by one of the teams that discovered it and REST by the other, prevents neural stem cells from expressing about 60 genes that are required for the creation of nerve cells. When the double-stranded RNA connects with this protein, Gage says, a role reversal occurs: The protein triggers the same genes it once silenced.

“It looks as though [the RNA] is switching it from a repressor to an activator,” says Gage.

His group observed that the genes controlled by the RNA-protein union also contain a DNA sequence needed to make the unusual RNA itself. That raises the prospect that the DNA, RNA, and protein together form a complex that initiates gene activity, says Gage.

“There aren’t enough data to know what the mechanism is at this point,” says Gail Mandel of the State University of New York at Stony Brook, one of the discoverers of the NRSF/REST protein.

She, however, favors a model in which the newfound RNA’s attachment to NRSF/REST causes the protein to detach from the genes it represses rather than to change into a gene activator.

Gage’s study “intersects two really important and emerging areas: noncoding RNAs and stem cell differentiation,” says Mandel. “It’s a really compelling story. It fits into the general idea that we’ve underestimated what RNAs can do in the genome and what their contributions are to gene expression.”

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