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.
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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.
Kim J, Krichevsky A, Grad Y, Hayes GD, Kosik KS, Church GM, Ruvkun G.
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.
Nelson PT, Wang WX, Wilfred BR, Tang G.
Technical variables in high-throughput miRNA expression profiling: much work remains to be done.
Biochim Biophys Acta. 2008 Nov;1779(11):758-65.
Alzheimer's disease as homeostatic responses to age-related myelin breakdown.
Neurobiol Aging. 2011 Aug;32(8):1341-71.
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.
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).
Davis TH, Cuellar TL, Koch SM, Barker AJ, Harfe BD, McManus MT, Ullian EM.
Conditional loss of Dicer disrupts cellular and tissue morphogenesis in the cortex and hippocampus.
J Neurosci. 2008 Apr 23;28(17):4322-30.
Putative Role of MicroRNA-Regulated Pathways in Comorbid Neurological and Cardiovascular Disorders.
Cardiovasc Psychiatry Neurol. 2009;2009:849519.
Junker A, Krumbholz M, Eisele S, Mohan H, Augstein F, Bittner R, Lassmann H, Wekerle H, Hohlfeld R, Meinl E.
MicroRNA profiling of multiple sclerosis lesions identifies modulators of the regulatory protein CD47.
Brain. 2009 Dec;132(Pt 12):3342-52.
Kocerha J, Faghihi MA, Lopez-Toledano MA, Huang J, Ramsey AJ, Caron MG, Sales N, Willoughby D, Elmen J, Hansen HF, Orum H, Kauppinen S, Kenny PJ, Wahlestedt C.
MicroRNA-219 modulates NMDA receptor-mediated neurobehavioral dysfunction.
Proc Natl Acad Sci U S A. 2009 Mar 3;106(9):3507-12.
Siegel G, Obernosterer G, Fiore R, Oehmen M, Bicker S, Christensen M, Khudayberdiev S, Leuschner PF, Busch CJ, Kane C, Hübel K, Dekker F, Hedberg C, Rengarajan B, Drepper C, Waldmann H, Kauppinen S, Greenberg ME, Draguhn A, Rehmsmeier M, Martinez J, Schratt GM.
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.
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