In this latest series of experiments, Dugas, Barres and their colleagues showed that impairing all microRNA production in cells fated to become oligodendrocytes produced both behavioral defects in live laboratory mice and clear anatomical defects (lack of proper myelination) in brain slices from these mice. Precursor cells cultured in a dish failed to undergo the conversion to adulthood normally triggered by withdrawal of a growth factor, which stimulates precursor cells' proliferation, from the culture medium.

Then, the scientists induced the oligodendrocyte precursor-to-adult transition in normal cells and, using the McManus lab's technology, checked for microRNAs whose levels changed greatly. The amount of one particular microRNA, miR-219, increased by 100-fold at this juncture, Dugas said. That finding has been confirmed in another laboratory that will also publish soon on this subject, Dugas and Barres said.

Staining of brain sections revealed that miR-219 is largely restricted to the brain's white matter - that is, its myelinated regions - making it an excellent biomarker for oligodendrocytes. The researchers also found that delivering a synthetic analog of miR-219 to oligodendrocyte precursor cells deficient in all microRNA generation - and therefore incapable of maturing to myelin-producing oligodendrocytes - partially rescued those cells' ability to mature. Moreover, knocking out only miR-219 function in the oligodendrocyte-fated precursor cells once again prevented them from maturing normally. Adding miR-219 to normal oligodendrocyte precursors in culture, without inducing their differentiation by standard growth-factor withdrawal, increased up to fourfold their likelihood of converting to adulthood.

Finally, the investigators were able to identify several distinct messenger RNAs that were inhibited by miR-219. These messenger RNAs encode proteins that both maintain precursors' proliferative potential and prevent them from becoming full-fledged oligodendrocytes.

"In addition to potential importance for stimulating remyelination in multiple sclerosis, we're especially excited about our findings' potential significance for glioma, the most common adult brain tumor," Barres said. "There hasn't been any really good treatment for these tumors, in which precursor cells start dividing and dividing and don't differentiate. Why are these cells behaving so abnormally? Maybe this microRNA switch has been downregulated or shut down entirely. Perhaps by introducing miR-219 back into glioma cells, we may actually be able to stop them from behaving like tumor cells." Barres said his lab has entered into a collaboration with another group to test this idea.

Source: Stanford University Medical Center