دورية أكاديمية
Loss of Tuberous Sclerosis Complex1 in Adult Oligodendrocyte Progenitor Cells Enhances Axon Remyelination and Increases Myelin Thickness after a Focal Demyelination.
| العنوان: | Loss of Tuberous Sclerosis Complex1 in Adult Oligodendrocyte Progenitor Cells Enhances Axon Remyelination and Increases Myelin Thickness after a Focal Demyelination. |
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| المؤلفون: | McLane LE; Department of Pharmacology, Physiology, and Neuroscience and Cancer Center, New Jersey Medical School, Rutgers University, Newark, New Jersey 07101, and., Bourne JN; Department of Cell and Developmental Biology, University of Colorado School of Medicine, Aurora, Colorado 80045., Evangelou AV; Department of Pharmacology, Physiology, and Neuroscience and Cancer Center, New Jersey Medical School, Rutgers University, Newark, New Jersey 07101, and., Khandker L; Department of Pharmacology, Physiology, and Neuroscience and Cancer Center, New Jersey Medical School, Rutgers University, Newark, New Jersey 07101, and., Macklin WB; Department of Cell and Developmental Biology, University of Colorado School of Medicine, Aurora, Colorado 80045., Wood TL; Department of Pharmacology, Physiology, and Neuroscience and Cancer Center, New Jersey Medical School, Rutgers University, Newark, New Jersey 07101, and Terri.wood@rutgers.edu. |
| المصدر: | The Journal of neuroscience : the official journal of the Society for Neuroscience [J Neurosci] 2017 Aug 02; Vol. 37 (31), pp. 7534-7546. Date of Electronic Publication: 2017 Jul 10. |
| نوع المنشور: | Journal Article; Research Support, Non-U.S. Gov't; Research Support, N.I.H., Extramural |
| اللغة: | English |
| بيانات الدورية: | Publisher: Society for Neuroscience Country of Publication: United States NLM ID: 8102140 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1529-2401 (Electronic) Linking ISSN: 02706474 NLM ISO Abbreviation: J Neurosci Subsets: MEDLINE |
| أسماء مطبوعة: | Publication: Washington, DC : Society for Neuroscience Original Publication: [Baltimore, Md.] : The Society, c1981- |
| مواضيع طبية MeSH: | Demyelinating Diseases/*metabolism , Demyelinating Diseases/*pathology , Nerve Fibers, Myelinated/*pathology , Oligodendroglia/*metabolism , Oligodendroglia/*pathology , Stem Cells/*metabolism , Tumor Suppressor Proteins/*metabolism, Animals ; Axons ; Cell Differentiation/physiology ; Cells, Cultured ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Myelin Sheath/metabolism ; Myelin Sheath/pathology ; Nerve Fibers, Myelinated/metabolism ; Nerve Regeneration/physiology ; Stem Cells/pathology ; Tuberous Sclerosis Complex 1 Protein |
| مستخلص: | Although the mammalian target of rapamycin (mTOR) is an essential regulator of developmental oligodendrocyte differentiation and myelination, oligodendrocyte-specific deletion of tuberous sclerosis complex (TSC), a major upstream inhibitor of mTOR, surprisingly also leads to hypomyelination during CNS development. However, the function of TSC has not been studied in the context of remyelination. Here, we used the inducible Cre-lox system to study the function of TSC in the remyelination of a focal, lysolecithin-demyelinated lesion in adult male mice. Using two different mouse models in which Tsc1 is deleted by Cre expression in oligodendrocyte progenitor cells (OPCs) or in premyelinating oligodendrocytes, we reveal that deletion of Tsc1 affects oligodendroglia differently depending on the stage of the oligodendrocyte lineage. Tsc1 deletion from NG2 + OPCs accelerated remyelination. Conversely, Tsc1 deletion from proteolipid protein (PLP)-positive oligodendrocytes slowed remyelination. Contrary to developmental myelination, there were no changes in OPC or oligodendrocyte numbers in either model. Our findings reveal a complex role for TSC in oligodendrocytes during remyelination in which the timing of Tsc1 deletion is a critical determinant of its effect on remyelination. Moreover, our findings suggest that TSC has different functions in developmental myelination and remyelination. SIGNIFICANCE STATEMENT Myelin loss in demyelinating disorders such as multiple sclerosis results in disability due to loss of axon conductance and axon damage. Encouragingly, the nervous system is capable of spontaneous remyelination, but this regenerative process often fails. Many chronically demyelinated lesions have oligodendrocyte progenitor cells (OPCs) within their borders. It is thus of great interest to elucidate mechanisms by which we might enhance endogenous remyelination. Here, we provide evidence that deletion of Tsc1 from OPCs, but not differentiating oligodendrocytes, is beneficial to remyelination. This finding contrasts with the loss of oligodendroglia and hypomyelination seen with Tsc1 or Tsc2 deletion in the oligodendrocyte lineage during CNS development and points to important differences in the regulation of developmental myelination and remyelination. (Copyright © 2017 the authors 0270-6474/17/377534-13$15.00/0.) |
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| معلومات مُعتمدة: | R01 NS082203 United States NS NINDS NIH HHS; R37 NS082203 United States NS NINDS NIH HHS |
| فهرسة مساهمة: | Keywords: NG2; TSC; adult OPCs; mTOR; remyelination |
| المشرفين على المادة: | 0 (Tsc1 protein, mouse) 0 (Tuberous Sclerosis Complex 1 Protein) 0 (Tumor Suppressor Proteins) |
| تواريخ الأحداث: | Date Created: 20170712 Date Completed: 20170822 Latest Revision: 20190629 |
| رمز التحديث: | 20231215 |
| مُعرف محوري في PubMed: | PMC5546116 |
| DOI: | 10.1523/JNEUROSCI.3454-16.2017 |
| PMID: | 28694334 |
| قاعدة البيانات: | MEDLINE |
| تدمد: | 1529-2401 |
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| DOI: | 10.1523/JNEUROSCI.3454-16.2017 |