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      HDAC-mediated Deacetylation of NF-κB is Critical for Schwann cell Myelination

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          Abstract

          Schwann cell myelination is tightly regulated by timely expression of key transcriptional regulators that respond to specific environmental cues, yet molecular mechanisms underlying such a process are poorly understood. Here, we report that HDAC1/2-regulated acetylation state of NF-κB is critical in orchestrating the myelination program. Mice lacking HDAC1/2 exhibit severe dysmyelination with Schwann cell development arrested at the immature stage. We find that NF-κB p65 becomes heavily acetylated in HDAC1/2 mutants, inhibiting the expression of positive regulators of myelination, while inducing the expression of differentiation inhibitors. We observe that NF-κB protein complex switches its association with p300 to that with HDAC1/2 as Schwann cells differentiate. NF-κB and HDAC1/2 act coordinately to regulate the transcriptionally-linked chromatin state for Schwann cell myelination. Thus, our results reveal an HDAC-mediated developmental switch for controlling myelination in the peripheral nervous system.

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          Most cited references 14

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          The diverse functions of histone lysine methylation.

          Covalent modifications of histone tails have fundamental roles in chromatin structure and function. One such modification, lysine methylation, has important functions in many biological processes that include heterochromatin formation, X-chromosome inactivation and transcriptional regulation. Here, we summarize recent advances in our understanding of how lysine methylation functions in these diverse biological processes, and raise questions that need to be addressed in the future.
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            The origin and development of glial cells in peripheral nerves.

            During the development of peripheral nerves, neural crest cells generate myelinating and non-myelinating glial cells in a process that parallels gliogenesis from the germinal layers of the CNS. Unlike central gliogenesis, neural crest development involves a protracted embryonic phase devoted to the generation of, first, the Schwann cell precursor and then the immature Schwann cell, a cell whose fate as a myelinating or non-myelinating cell has yet to be determined. Embryonic nerves therefore offer a particular opportunity to analyse the early steps of gliogenesis from transient multipotent stem cells, and to understand how this process is integrated with organogenesis of peripheral nerves.
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              Dysregulation of the Wnt pathway inhibits timely myelination and remyelination in the mammalian CNS.

              The progressive loss of CNS myelin in patients with multiple sclerosis (MS) has been proposed to result from the combined effects of damage to oligodendrocytes and failure of remyelination. A common feature of demyelinated lesions is the presence of oligodendrocyte precursors (OLPs) blocked at a premyelinating stage. However, the mechanistic basis for inhibition of myelin repair is incompletely understood. To identify novel regulators of OLP differentiation, potentially dysregulated during repair, we performed a genome-wide screen of 1040 transcription factor-encoding genes expressed in remyelinating rodent lesions. We report that approximately 50 transcription factor-encoding genes show dynamic expression during repair and that expression of the Wnt pathway mediator Tcf4 (aka Tcf7l2) within OLPs is specific to lesioned-but not normal-adult white matter. We report that beta-catenin signaling is active during oligodendrocyte development and remyelination in vivo. Moreover, we observed similar regulation of Tcf4 in the developing human CNS and lesions of MS. Data mining revealed elevated levels of Wnt pathway mRNA transcripts and proteins within MS lesions, indicating activation of the pathway in this pathological context. We show that dysregulation of Wnt-beta-catenin signaling in OLPs results in profound delay of both developmental myelination and remyelination, based on (1) conditional activation of beta-catenin in the oligodendrocyte lineage in vivo and (2) findings from APC(Min) mice, which lack one functional copy of the endogenous Wnt pathway inhibitor APC. Together, our findings indicate that dysregulated Wnt-beta-catenin signaling inhibits myelination/remyelination in the mammalian CNS. Evidence of Wnt pathway activity in human MS lesions suggests that its dysregulation might contribute to inefficient myelin repair in human neurological disorders.
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                Author and article information

                Journal
                9809671
                21092
                Nat Neurosci
                Nature neuroscience
                1097-6256
                1546-1726
                23 February 2011
                20 March 2011
                April 2011
                1 October 2011
                : 14
                : 4
                : 437-441
                Affiliations
                [1 ]Department of Developmental Biology and Kent Waldrep Foundation Center for Basic Neuroscience Research on Nerve Growth and Regeneration, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
                [2 ]Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
                [3 ]Department of Molecular and Cellular Biochemistry, Center for Molecular Neurobiology, The Ohio State University, Columbus, Ohio 43210, USA.
                [4 ]Institute of Veterinary Biochemistry and Molecular Biology, University of Zurich, 8057 Zurich, Switzerland.
                [5 ]Department of Comparative Biosciences, and the Waisman Center, University of Wisconsin, Madison, Wisconsin 53705.
                [6 ]Max-Planck-Institute of Experimental Medicine, Department of Neurogenetics, D-37075 Goettingen, Germany.
                [7 ]Department of Biological Sciences, Rutgers University, Newark, NJ 07102, USA.
                Author notes
                Corresponding author: qrichard.lu@ 123456utsouthwestern.edu Tel: 214-648-7410; Fax: 214-648-1960
                Article
                nihpa274762
                10.1038/nn.2780
                3074381
                21423191

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                Funding
                Funded by: National Institute of Neurological Disorders and Stroke : NINDS
                Award ID: R01 NS072427-02 ||NS
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