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.

References:
Zhao X, He X, Han X, Yu Y, Ye F, Chen Y, Hoang TN, Xu X, Mi Q-S, Xin M, Wang F, Appel B, Lu QR. MicroRNA-mediated control of oligodendrocyte differentiation. Neuron 2010, March 11; 65:612-626. Abstract

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, March 11; 65:597-611. Abstract

Nave KA. Oligodendrocytes and the “Micro Brake” of progenitor cell proliferation. Neuron 2010, March 11; 65:577-579. Abstract

Comments

Make a Comment

To make a comment you must login or register.

Comments on this content

  1. These papers contain nice work. Since the work comes “in stereo” in a great journal, it seems all the more significant. It's rare but not unprecedented to see such similar cutting-edge research from two excellent labs.

    I think these data are potentially very important. They harken back to a classical, almost a decade-old paradigm for miRNAs, namely that they are somewhat like bookmarks for a developmental stage of a particular cell lineage. miRNAs were discovered in animals in the context of the heterochronic developmental pathway in worm. Here the miRNAs regulated transcription factors, for example, the worm gene lin-14, and thus exerted a great impact on cell and organism phenotype.

    In the meantime, expectations for miRNAs have broadened in terms of CNS roles, as it has been shown that miRNAs can exist as dynamic regulators of cell function in addition to assisting in the progression or maintenance of developmental states. However, both papers by Zhao et al. and Dugas et al. in Neuron suggest that the paradigm of developmental pathways needs to be kept in mind in the mammalian CNS in which miRNAs regulate transcription factors for stage-specific lineage specificity.

    One thing I note about these miRNAs is that they are considered in these papers to be “oligodendrocyte-specific.” This gives me pause. miR-338 was isolated from primary rat cerebral cortical cultures (Kim et al., 2004), and we have found that miR-219 is relatively enriched in hippocampal neuronal cultures relative to glial cultures (Wang et al., 2008). This puzzling question of miRNA cell type “specificity” is explicitly, but not completely, addressed in the papers being discussed. It seems to underscore the fact that a particular miRNA, much like a particular protein, can have distinct functions in different contexts.

    Also, since the oligodendrocyte is a hitherto understudied potential focal point of pathogenesis (see, e.g., the recent studies by George Bartzokis concerning the potential role(s) of oligodendrocyte dysfunction in Alzheimer disease; Bartzokis, 2009), it remains to be seen if miRNAs may participate in these pathological processes.

    References:

    . Identification of many microRNAs that copurify with polyribosomes in mammalian neurons. Proc Natl Acad Sci U S A. 2004 Jan 6;101(1):360-5. PubMed.

    . Technical variables in high-throughput miRNA expression profiling: much work remains to be done. Biochim Biophys Acta. 2008 Nov;1779(11):758-65. PubMed.

    . Alzheimer's disease as homeostatic responses to age-related myelin breakdown. Neurobiol Aging. 2011 Aug;32(8):1341-71. PubMed.

  2. I read these two papers with great interest. They are elegant and provide
    definitive molecular explanations underlying the developmental switch from
    proliferating OPCs to differentiating OPCs. Cell-cycle exit is often coupled
    with the initiation of differentiation in different types of cells. These
    observations suggest a possible involvement of microRNA-dependent processes. It will be interesting to find out in future studies how microRNA biogenesis, for example, that of miR-219 in oligodendrocytes, is regulated.

  3. These two new studies highlight once again the importance of Dicer and microRNAs in brain function. Perhaps expectedly, the authors demonstrate in a convincing way that mammalian Dicer is required for oligodendrocyte differentiation and myelination. Here, a combination of three independent mouse Cre lines was used to study the effects of Dicer loss in oligodendrocyte/Schwann cells. Interestingly, the ataxia and tremor behaviors present in the mutant mice were previously observed in CaMkII-Cre mice, in which Dicer was deleted in pyramidal neurons (Davis et al., 2008; Hebert et al., unpublished).

    A few candidate microRNAs, including miR-338, miR-138, and more particularly miR-219, seem important for the loss-of-function phenotype in the Dicer cKO mice. These conclusions are based on miRNA profiling and rescue experiments on isolated cultured cells and in vivo. The partial rescue by candidate miRNAs may be related to technical issues or, more likely, to requirement of additional miRNAs in oligodendrocyte differentiation and function.

    Interestingly, previous reports have shown that miR-219 and miR-138 are functionally expressed in neurons (Kocerha et al., 2009; Siegel et al., 2009). Indeed, miR-219 seems important for NMDA receptor signaling, whereas miR-138 controls dendritic spine morphology. Although one must be careful in the interpretation of cell “enriched” or “specific” (i.e., 10 and 100 times, respectively, more abundant when compared to other tissues), these miRNAs are clearly highly expressed in the brain. It remains possible that these miRNAs share different subcellular localization, depending on cell type. For instance, miR-138 is enriched in neuronal dendrites (Siegel et al., 2009).

    Is miR-219 physiologically more important in oligodendrocytes compared to neurons? Not necessarily. In addition to cell-type specificity, the organism has developed many ways to control miRNA function, including developmental timing, subcellular localization, relative expression levels, and post-transcriptional modifications. Complex organs such as the brain have likely developed an additional level of miRNA regulation based on cell-specific gene targets, perhaps using a combination of unique co-factors. In this way, the same miRNA could target different genes depending on cellular context. Of course, this line of thinking could be extrapolated to ubiquitously expressed miRNAs. In accordance with this hypothesis, it has been proposed that the “brain-specific” miR-29 could play an important role in various cardiovascular diseases (Hebert, 2009). More related to these studies, microarray studies have shown that ubiquitously expressed miR-20 family members (miR-20a, miR-106a, and miR-R17-5p) are downregulated in Dicer-deficient oligodendrocytes.

    Whether miR-219 and/or other candidate miRNAs are specifically involved in myelination diseases in humans remains an attractive possibility. Interestingly, changes in miRNA expression levels have been associated with multiple sclerosis, including downregulation of miR-219 and miR-338 (Junker et al., 2009).

    References:

    . Conditional loss of Dicer disrupts cellular and tissue morphogenesis in the cortex and hippocampus. J Neurosci. 2008 Apr 23;28(17):4322-30. PubMed.

    . Putative Role of MicroRNA-Regulated Pathways in Comorbid Neurological and Cardiovascular Disorders. Cardiovasc Psychiatry Neurol. 2009;2009:849519. PubMed.

    . MicroRNA profiling of multiple sclerosis lesions identifies modulators of the regulatory protein CD47. Brain. 2009 Dec;132(Pt 12):3342-52. PubMed.

    . MicroRNA-219 modulates NMDA receptor-mediated neurobehavioral dysfunction. Proc Natl Acad Sci U S A. 2009 Mar 3;106(9):3507-12. PubMed.

    . A functional screen implicates microRNA-138-dependent regulation of the depalmitoylation enzyme APT1 in dendritic spine morphogenesis. Nat Cell Biol. 2009 Jun;11(6):705-16. PubMed.

Comments on Primary Papers for this Article

No Available Comments on Primary Papers for this Article

References

Paper Citations

  1. . 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.
  2. . MicroRNA-mediated control of oligodendrocyte differentiation. Neuron. 2010 Mar 11;65(5):612-26. PubMed.
  3. . Dicer1 and miR-219 Are required for normal oligodendrocyte differentiation and myelination. Neuron. 2010 Mar 11;65(5):597-611. PubMed.
  4. . Oligodendrocytes and the "micro brake" of progenitor cell proliferation. Neuron. 2010 Mar 11;65(5):577-9. PubMed.

Further Reading

Papers

  1. . Dicer1 and miR-219 Are required for normal oligodendrocyte differentiation and myelination. Neuron. 2010 Mar 11;65(5):597-611. PubMed.
  2. . MicroRNA-mediated control of oligodendrocyte differentiation. Neuron. 2010 Mar 11;65(5):612-26. PubMed.
  3. . Oligodendrocytes and the "micro brake" of progenitor cell proliferation. Neuron. 2010 Mar 11;65(5):577-9. PubMed.

News

  1. Paris: Macro-roles for MicroRNAs in the Life and Death of Neurons
  2. BACE in Alzheimer’s—Does MicroRNA Control Translation?
  3. Muscle MicroRNA Repairs Nerve-Muscle Connection in ALS Model
  4. Keystone: More Than Mere Nucleotides—miRNAs as Master Regulators, Part 1
  5. Keystone: More Than Mere Nucleotides—miRNAs as Master Regulators, Part 2
  6. DC: More MicroRNA Implicated in Dementia
  7. Research Brief: MicroRNA Muscles In on Synaptic Regulation

Primary Papers

  1. . Dicer1 and miR-219 Are required for normal oligodendrocyte differentiation and myelination. Neuron. 2010 Mar 11;65(5):597-611. PubMed.
  2. . MicroRNA-mediated control of oligodendrocyte differentiation. Neuron. 2010 Mar 11;65(5):612-26. PubMed.
  3. . Oligodendrocytes and the "micro brake" of progenitor cell proliferation. Neuron. 2010 Mar 11;65(5):577-9. PubMed.