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      miR-124 regulates adult neurogenesis in the SVZ stem cell niche

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          Abstract

          The subventricular zone (SVZ) is the largest neurogenic niche in the adult mammalian brain. Here we show that the brain-enriched microRNA miR-124 is an important regulator of the temporal progression of adult neurogenesis in mice. Knockdown of endogenous miR-124 maintains purified SVZ stem cells as dividing precursors, whereas ectopic expression leads to precocious and increased neuron formation. Furthermore, blocking miR-124 function during regeneration leads to hyperplasias followed by a delayed burst of neurogenesis. We identify the SRY-box transcription factor Sox9 to be a physiological target of miR-124 at the transition from transit amplifying cell to neuroblast stage. Sox9 over-expression abolishes neuronal differentiation whereas Sox9 knockdown leads to increased neuron formation. Thus, miR-124 mediated repression of Sox9 is important for progression along the SVZ stem cell lineage to neurons.

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          Microarray analysis shows that some microRNAs downregulate large numbers of target mRNAs.

          Lee P. Lim, Nelson C. Lau, Philip Garrett-Engele … (2005)
          MicroRNAs (miRNAs) are a class of noncoding RNAs that post-transcriptionally regulate gene expression in plants and animals. To investigate the influence of miRNAs on transcript levels, we transfected miRNAs into human cells and used microarrays to examine changes in the messenger RNA profile. Here we show that delivering miR-124 causes the expression profile to shift towards that of brain, the organ in which miR-124 is preferentially expressed, whereas delivering miR-1 shifts the profile towards that of muscle, where miR-1 is preferentially expressed. In each case, about 100 messages were downregulated after 12 h. The 3' untranslated regions of these messages had a significant propensity to pair to the 5' region of the miRNA, as expected if many of these messages are the direct targets of the miRNAs. Our results suggest that metazoan miRNAs can reduce the levels of many of their target transcripts, not just the amount of protein deriving from these transcripts. Moreover, miR-1 and miR-124, and presumably other tissue-specific miRNAs, seem to downregulate a far greater number of targets than previously appreciated, thereby helping to define tissue-specific gene expression in humans.
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            Prediction of mammalian microRNA targets.

            Benjamin Lewis, I-hung Shih, Matthew W Jones-Rhoades … (2003)
            MicroRNAs (miRNAs) can play important gene regulatory roles in nematodes, insects, and plants by basepairing to mRNAs to specify posttranscriptional repression of these messages. However, the mRNAs regulated by vertebrate miRNAs are all unknown. Here we predict more than 400 regulatory target genes for the conserved vertebrate miRNAs by identifying mRNAs with conserved pairing to the 5' region of the miRNA and evaluating the number and quality of these complementary sites. Rigorous tests using shuffled miRNA controls supported a majority of these predictions, with the fraction of false positives estimated at 31% for targets identified in human, mouse, and rat and 22% for targets identified in pufferfish as well as mammals. Eleven predicted targets (out of 15 tested) were supported experimentally using a HeLa cell reporter system. The predicted regulatory targets of mammalian miRNAs were enriched for genes involved in transcriptional regulation but also encompassed an unexpectedly broad range of other functions.
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              The MicroRNA miR-124 promotes neuronal differentiation by triggering brain-specific alternative pre-mRNA splicing.

              Eugene V. Makeyev, Jiangwen Zhang, Monica A. Carrasco … (2007)
              Both microRNAs and alternative pre-mRNA splicing have been implicated in the development of the nervous system (NS), but functional interactions between these two pathways are poorly understood. We demonstrate that the neuron-specific microRNA miR-124 directly targets PTBP1 (PTB/hnRNP I) mRNA, which encodes a global repressor of alternative pre-mRNA splicing in nonneuronal cells. Among the targets of PTBP1 is a critical cassette exon in the pre-mRNA of PTBP2 (nPTB/brPTB/PTBLP), an NS-enriched PTBP1 homolog. When this exon is skipped, PTBP2 mRNA is subject to nonsense-mediated decay (NMD). During neuronal differentiation, miR-124 reduces PTBP1 levels, leading to the accumulation of correctly spliced PTBP2 mRNA and a dramatic increase in PTBP2 protein. These events culminate in the transition from non-NS to NS-specific alternative splicing patterns. We also present evidence that miR-124 plays a key role in the differentiation of progenitor cells to mature neurons. Thus, miR-124 promotes NS development, at least in part by regulating an intricate network of NS-specific alternative splicing.
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                Author and article information

                Journal
                Journal ID (nlm-journal-id): 9809671
                Journal ID (pubmed-jr-id): 21092
                Journal ID (nlm-ta): Nat Neurosci
                Title: Nature neuroscience
                ISSN (Print): 1097-6256
                ISSN (Electronic): 1546-1726
                Publication date Nihms-submitted: 28 April 2009
                Publication date (Electronic): 15 March 2009
                Publication date (Print): April 2009
                Publication date PMC-release: 23 October 2009
                Volume: 12
                Issue: 4
                Pages: 399-408
                Affiliations
                [1 ]Department of Pathology and Cell Biology, Columbia University, College of Physician and Surgeons, 630 West 168 th Street, New York 10032
                [2 ]Department of Neuroscience, Columbia University, College of Physician and Surgeons, 630 West 168 th Street, New York 10032
                [3 ]Department of Neurology, Columbia University, College of Physician and Surgeons, 630 West 168 th Street, New York 10032
                [4 ]Center for Motor Neuron Biology and Disease, Columbia University, College of Physician and Surgeons, 630 West 168 th Street, New York 10032
                Author notes
                [§ ]Corresponding author, Fiona Doetsch, Ph: (212) 342-5633, Fax: (212) 305-5498 fkd2101@ 123456columbia.edu

                Author contributions

                L.C. and F.D. initiated the project. L.C. generated pSR-GFP, pSR-124mt and pSR-shRNA constructs. L.C. and M.T. generated pSR-124. M.T. and E.P. generated pQC-Sox9. L.C. performed the in situ hybridization, qRT-PCR, neurosphere assays, neuron survival assays, Sox9 expression assay, retroviral production, penetratin conjugation, in vivo delivery and Ara-C experiments. L.C. and E.P. performed the FACS sorting, co-cultures, adherent cultures and in vivo injections. E.P. performed the Gene Ontology studies. M.T. performed the luciferase assays and Sox9 immunohistochemistry. F.D. was involved in study design, data collection, quantification and data analysis. The manuscript was written by F.D., L.C. and E.P. All authors performed data quantification, discussed the results and commented on the manuscript.

                Article
                Manuscript ID: nihpa103137
                DOI: 10.1038/nn.2294
                PMC ID: 2766245
                PubMed ID: 19287386
                SO-VID: 56c02e76-9dd1-475a-bb01-a274037fe68b
                History
                Funding
                Funded by: National Institute of Mental Health : NIMH
                Award ID: T32 MH015174-32 ||MH
                Categories
                Subject: Article

                ScienceOpen disciplines: Neurosciences
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                ScienceOpen disciplines: Neurosciences

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