Don’t let the name fool you. There’s nothing minor about microRNAs. In one fell swoop, a single one can modulate the synthesis of tens, or perhaps hundreds, of proteins. Is it any wonder that these newest members of the RNA family have turned out to be master regulators of basic biology? If you still need convincing, check out the back-to-back microRNA (miRNA) papers in yesterday’s Neuron. Working independently, two research groups have discovered why oligodendrocyte precursor cells suddenly stop proliferating and start producing myelin. The answer is an miRNA switch that simultaneously turns off proliferation and turns on maturation. The findings not only show the power that a few miRNAs can wield, but it also may help scientists better understand why oligodendrocytes sometimes go awry, as in gliomas and bouts of demyelination, which can occur in Alzheimer disease.
During development, oligodendrocyte precursor cells (OPCs) rapidly migrate and expand into white matter tracts in the central nervous system. As Klaus-Armin Nave, Max Planck Institute of Experimental Medicine, Goettingen, Germany, notes in a Neuron Preview that accompanies the two papers, they then switch abruptly from being proliferating OPCs to become mature myelinating oligodendrocytes (OLs). Uncannily, this change occurs just when axon and OPC numbers seem to match. It occurs even in the presence of strong OPC proliferating stimuli, such as platelet-derived growth factor (PDGF). Scientists have puzzled over what flips that switch. “Since miRNAs have shown up as regulators of all sorts of biological systems, it made sense to see if they are involved,” said Jason Dugas, who, together with Ben Barres at Stanford University, California, led one of the research groups. The other was led by Richard Lu at the University of Texas Southwestern Medical Center, Dallas.
Both groups took similar approaches to address the role of miRNAs in OL maturation, and they turned up very similar answers. Working with Lu, first author Xianghui Zhao and colleagues asked what happens if miRNAs are completely abolished from all oligodendrocytes. The researchers focused on Dicer1, an enzyme essential for processing larger RNA precursors into the smaller, active 20-24 nucleotide microRNAs. Knocking out this enzyme in the OPC lineage in mice, Zhao found that animals were born without myelin and died after around three weeks. Dugas’s group also knocked out Dicer1 in mouse oligodendrocytes, finding a shiverer phenotype typical of animals lacking myelin. These mice survived better than did Zhao’s knockouts, and curiously, as they aged they began to behave like normal littermates. Dugas found that a significant proportion of myelinating oligodendrocytes survived with Dicer1 intact, suggesting that clonal expansion of those cells as the animals aged was sufficient to restore myelination where it’s needed.
That both groups found Dicer1 to be essential for proper myelination indicates that miRNAs are most likely involved. But which of the thousand or so found in mammals could it be? Here, the strategies of the two groups diverged slightly. Dugas and colleagues looked for miRNAs in mature OLs that are not present in immature cells of the same lineage, whereas Zhao and colleagues compared miRNA expression in spinal cord tissues that do and do not contain oligodendrocytes. While both groups found that three miRNAs—miR-219, miR-138, and miR-338—were robustly induced in oligodendrocytes, they differed slightly in which ones seemed more important for the maturation switch. Zhao’s work suggests that miR-219 and miR-338 promote precursor differentiation, while Dugas’s group fingered miR-219 and miR-138. Dugas thinks all three miRNAs may be important, and that the different findings may be due to slightly different methodologies or even reagents.
But how might these three miRNAs flip the maturation switch? Because microRNAs act as translational modulators, the scientists looked to messenger RNAs predicted to have complementary sequences. These include a PDGF receptor and two transcription factors that block OL maturation—Sox6 and Hes5. Looking at results of both groups, it appears that miR-219 blocks translation of all three proteins. Other potential targets of lesser known function cropped up as well, including the transcription factors FoxJ3 and ZFP238 (also known as RP58).
Dugas believes that these findings are relevant to gliomas and perhaps human diseases where myelin is compromised, which could include AD. Imaging data suggest a loss of myelin in white matter tracts as the disease progresses (see Bartzokis et al., 2003). Nave wonders if miRNAs themselves might be culpable. “Given the sensitivity of all myelinating glia to the overexpression of myelin membrane proteins and the intriguing finding that a clinically relevant myelin protein, PMP22, is regulated by miR-29A, one wonders how soon miRNAs themselves will be associated with a human myelin disease,” he writes.—Tom Fagan
- Bartzokis G, Cummings JL, Sultzer D, Henderson VW, Nuechterlein KH, Mintz J. White matter structural integrity in healthy aging adults and patients with Alzheimer disease: a magnetic resonance imaging study. Arch Neurol. 2003 Mar;60(3):393-8. PubMed.
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- Dugas JC, Cuellar TL, Scholze A, Ason B, Ibrahim A, Emery B, Zamanian JL, Foo LC, McManus MT, Barres BA. Dicer1 and miR-219 Are required for normal oligodendrocyte differentiation and myelination. Neuron. 2010 Mar 11;65(5):597-611. PubMed.
- Zhao X, He X, Han X, Yu Y, Ye F, Chen Y, Hoang T, Xu X, Mi QS, Xin M, Wang F, Appel B, Lu QR. MicroRNA-mediated control of oligodendrocyte differentiation. Neuron. 2010 Mar 11;65(5):612-26. PubMed.
- Nave KA. Oligodendrocytes and the "micro brake" of progenitor cell proliferation. Neuron. 2010 Mar 11;65(5):577-9. PubMed.