17
views
0
recommends
+1 Recommend
0 collections
    0
    shares
      • Record: found
      • Abstract: found
      • Article: found
      Is Open Access

      Hypomyelination following deletion of Tsc2 in oligodendrocyte precursors

      research-article

      Read this article at

      Bookmark
          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

          Objective

          While abnormalities in myelin in tuberous sclerosis complex ( TSC) have been known for some time, recent imaging‐based data suggest myelin abnormalities may be independent of the pathognomonic cortical lesions (“tubers”). Multiple mouse models of TSC exhibit myelination deficits, though the cell types responsible and the mechanisms underlying the myelin abnormalities remain unclear.

          Methods

          To determine the role of alterations in mTOR signaling in myelination, we generated a conditional knockout ( CKO) mouse model using Cre‐recombinase and the Olig2 promoter to inactivate the Tsc2 gene in oligodendrocyte precursor cells.

          Results

          Characterization of myelin and myelin constituent proteins demonstrated a marked hypomyelination phenotype. Diffusion‐based magnetic resonance imaging studies were likewise consistent with hypomyelination. Hypomyelination was due in part to decreased myelinated axon density and myelin thickness as well as decreased oligodendrocyte numbers. Coincident with hypomyelination, an extensive gliosis was seen in both the cortex and white matter tracks, suggesting alterations in cell fate due to changes in mTOR activity in oligodendrocyte precursors. Despite a high‐frequency appendicular tremor and altered gait in CKO mice, no significant changes in activity, vocalizations, or anxiety‐like phenotypes were seen.

          Interpretation

          Our findings support a known role of mTOR signaling in regulation of myelination and demonstrate that increased mTORC1 activity early in development within oligodendrocytes results in hypomyelination and not hypermyelination. Our data further support a dissociation between decreased Akt activity and increased mTORC1 activity toward hypomyelination. Thus, therapies promoting activation of Akt‐dependent pathways while reducing mTORC1 activity may prove beneficial in treatment of human disease.

          Related collections

          Most cited references38

          • Record: found
          • Abstract: found
          • Article: not found

          Disruption of Cnp1 uncouples oligodendroglial functions in axonal support and myelination.

          Myelination of axons by oligodendrocytes enables rapid impulse propagation in the central nervous system. But long-term interactions between axons and their myelin sheaths are poorly understood. Here we show that Cnp1, which encodes 2',3'-cyclic nucleotide phosphodiesterase in oligodendrocytes, is essential for axonal survival but not for myelin assembly. In the absence of glial cyclic nucleotide phosphodiesterase, mice developed axonal swellings and neurodegeneration throughout the brain, leading to hydrocephalus and premature death. But, in contrast to previously studied myelin mutants, the ultrastructure, periodicity and physical stability of myelin were not altered in these mice. Genetically, the chief function of glia in supporting axonal integrity can thus be completely uncoupled from its function in maintaining compact myelin. Oligodendrocyte dysfunction, such as that in multiple sclerosis lesions, may suffice to cause secondary axonal loss.
            Bookmark
            • Record: found
            • Abstract: found
            • Article: not found

            Differences in white matter fiber tract development present from 6 to 24 months in infants with autism.

            Evidence from prospective studies of high-risk infants suggests that early symptoms of autism usually emerge late in the first or early in the second year of life after a period of relatively typical development. The authors prospectively examined white matter fiber tract organization from 6 to 24 months in high-risk infants who developed autism spectrum disorders (ASDs) by 24 months. The participants were 92 high-risk infant siblings from an ongoing imaging study of autism. All participants had diffusion tensor imaging at 6 months and behavioral assessments at 24 months; a majority contributed additional imaging data at 12 and/or 24 months. At 24 months, 28 infants met criteria for ASDs and 64 infants did not. Microstructural properties of white matter fiber tracts reported to be associated with ASDs or related behaviors were characterized by fractional anisotropy and radial and axial diffusivity. The fractional anisotropy trajectories for 12 of 15 fiber tracts differed significantly between the infants who developed ASDs and those who did not. Development for most fiber tracts in the infants with ASDs was characterized by higher fractional anisotropy values at 6 months followed by slower change over time relative to infants without ASDs. Thus, by 24 months of age, those with ASDs had lower values. These results suggest that aberrant development of white matter pathways may precede the manifestation of autistic symptoms in the first year of life. Longitudinal data are critical to characterizing the dynamic age-related brain and behavior changes underlying this neurodevelopmental disorder.
              Bookmark
              • Record: found
              • Abstract: found
              • Article: not found

              In vivo visualization of myelin water in brain by magnetic resonance.

              We exploit the intrinsic difference in magnetic resonance spin-spin relaxation time, T2, between water associated with myelin sheaths and water in other central nervous system tissue in order to measure myelin water content within any region of an image or to generate indirectly a myelin map of the brain. In normal volunteers, myelin water maps give the expected myelin distribution. In multiple sclerosis patients, lesions exhibit different myelin water contents providing insight into the demyelination process unavailable from conventional magnetic resonance images. In vivo myelin measurement has important applications in the clinical management of multiple sclerosis and other white matter diseases.
                Bookmark

                Author and article information

                Journal
                Ann Clin Transl Neurol
                Ann Clin Transl Neurol
                10.1002/(ISSN)2328-9503
                ACN3
                Annals of Clinical and Translational Neurology
                John Wiley and Sons Inc. (Hoboken )
                2328-9503
                27 October 2015
                December 2015
                : 2
                : 12 ( doiID: 10.1111/acn3.2015.2.issue-12 )
                : 1041-1054
                Affiliations
                [ 1 ] Department of PediatricsVanderbilt University Nashville Tennessee
                [ 2 ] Department of Biomedical EngineeringVanderbilt University Nashville Tennessee
                Author notes
                [*] [* ] Correspondence

                Robert P. Carson, Department of Pediatrics, Vanderbilt University, Nashville, TN. Tel: 615‐936‐7567; Fax: 615‐343‐8407; E‐mail: robert.carson@ 123456vanderbilt.edu

                Article
                ACN3254
                10.1002/acn3.254
                4693589
                26734657
                28162d2d-e556-4186-94a1-967c9d96e67c
                © 2015 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals, Inc on behalf of American Neurological Association.

                This is an open access article under the terms of the Creative Commons Attribution‐NonCommercial‐NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.

                History
                : 17 June 2015
                : 14 August 2015
                : 27 August 2015
                Page count
                Pages: 14
                Funding
                Funded by: National Institute of Neurological Disorders and Stroke
                Funded by: National Institutes of Health
                Award ID: K08NS083710
                Award ID: 1R01 NS078289
                Funded by: Tuberous Sclerosis Alliance Postdoctoral Fellowship
                Categories
                Research Article
                Research Articles
                Custom metadata
                2.0
                acn3254
                December 2015
                Converter:WILEY_ML3GV2_TO_NLMPMC version:4.7.2 mode:remove_FC converted:22.12.2015

                Comments

                Comment on this article