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      Emerging Roles of Alternative Pre-mRNA Splicing Regulation in Neuronal Development and Function

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          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Abstract

          Alternative pre-mRNA splicing has the potential to greatly diversify the repertoire of transcripts in multicellular organisms. Increasing evidence suggests that this expansive layer of gene regulation plays a particularly important role in the development and function of the nervous system, one of the most complex organ systems found in nature. In this review, we highlight recent studies that continue to emphasize the influence and contribution of alternative splicing regulation to various aspects of neuronal development in addition to its role in the mature nervous system.

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          Most cited references 90

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          HITS-CLIP yields genome-wide insights into brain alternative RNA processing

          Summary Protein-RNA interactions play critical roles in all aspects of gene expression. Here we develop a genome-wide means of mapping protein-RNA binding sites in vivo, by high throughput sequencing of RNA isolated by crosslinking immunoprecipitation (HITS-CLIP). HITS-CLIP analysis of the neuron-specific splicing factor Nova2 revealed extremely reproducible RNA binding maps in multiple mouse brains. These maps provide genome-wide in vivo biochemical footprints confirming the previous prediction that the position of Nova binding determines the outcome of alternative splicing; moreover, they are sufficiently powerful to predict Nova action de novo. HITS-CLIP revealed a large number of Nova-RNA interactions in 3′ UTRs, leading to the discovery that Nova regulates alternative polyadenylation in the brain. HITS-CLIP, therefore, provides a robust, unbiased means to identify functional protein-RNA interactions in vivo.
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            The MicroRNA miR-124 promotes neuronal differentiation by triggering brain-specific alternative pre-mRNA splicing.

            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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              Alternative splicing: new insights from global analyses.

              Recent analyses of sequence and microarray data have suggested that alternative splicing plays a major role in the generation of proteomic and functional diversity in metazoan organisms. Efforts are now being directed at establishing the full repertoire of functionally relevant transcript variants generated by alternative splicing, the specific roles of such variants in normal and disease physiology, and how alternative splicing is coordinated on a global level to achieve cell- and tissue-specific functions. Recent progress in these areas is summarized in this review.
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                Author and article information

                Journal
                Front Neurosci
                Front. Neurosci.
                Frontiers in Neuroscience
                Frontiers Research Foundation
                1662-4548
                1662-453X
                16 June 2012
                21 August 2012
                2012
                : 6
                Affiliations
                1simpleFAS Center for Systems Biology, Harvard University Cambridge, MA, USA
                Author notes

                Edited by: Jernej Ule, MRC Laboratory of Molecular Biology, UK

                Reviewed by: Jiuyong Xie, The University of Manitoba, Canada; Jubao Duan, University of Chicago, USA

                *Correspondence: John A. Calarco, FAS Center for Systems Biology, Harvard University, 52 Oxford Street, Room 457.40, Cambridge, MA 02138, USA. e-mail: jcalarco@ 123456fas.harvard.edu

                This article was submitted to Frontiers in Neurogenomics, a specialty of Frontiers in Neuroscience.

                Article
                10.3389/fnins.2012.00122
                3424503
                22936897
                Copyright © 2012 Norris and Calarco.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in other forums, provided the original authors and source are credited and subject to any copyright notices concerning any third-party graphics etc.

                Page count
                Figures: 2, Tables: 0, Equations: 0, References: 108, Pages: 11, Words: 10359
                Categories
                Neuroscience
                Review Article

                Neurosciences

                alternative splicing, nervous system, genomics, gene regulation, rna processing

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