One of the many mysteries of stem cells is how they morph from a universal cell type, full of possibility, into one that's tailored for a specific job. Now scientists say they've hit on a startling explanation for some of these cells: A minuscule RNA molecule helps guide the early development of neurons and other brain cells. The finding is the latest addition to an ever-lengthening repertoire for small RNA molecules.
Small RNA molecules can bind to and blunt expression of DNA stretches with a complementary sequence. The first clues that they have a hand in stem cell development came in plants. Then scientists reported that members of a class of RNA molecules called microRNAs direct the development of blood and bone marrow cells in mice. These studies and others suggested that small RNAs play a leading role in development.
The possibility that they might be important in nerve cell development intrigued neuroscientists Fred Gage and Tomoko Kuwabara of the Salk Institute in La Jolla, California, and colleagues, who were studying how adult neural stem cells differentiate. The group probed human, adult neural stem cells for small RNA molecules and fished out more than 50 types. One double-stranded molecule stood out: It matched a DNA site that a protein key to neural development binds to. That protein, called NRSF, blocks the expression of 64 different genes and prevents them from turning a cell into a neuron. Furthermore, the team found, differentiating neural stem cells expressed the RNA at high levels, and introducing extra doses spurred neural stem cells to become neurons.
But when they probed how exactly this RNA did its job, the biologists uncovered something odd. The RNA was much more common in differentiated nerve cells than in neural stem cells--something that made little sense, because the RNA was linked to a protein that inhibited differentiation. Looking more closely, Gage's team found that rather than binding to DNA, as most small RNAs discovered so far do, this one bound to the NRSF protein and blunted its activity, they report in the 19 March issue of Cell.
"It's really breathtaking," says Steven Goldman, a neurologist and gene therapist at the University of Rochester in New York. "I think it will mark a paradigm shift" in how scientists understand stem cell differentiation, he adds. Gage says that he's still mystified over how the RNA he pinpointed so radically changes the function of the NRSF protein.