Oligodendrocyte PTEN is required for myelin and axonal integrity, not remyelination.
Oligodendrocyte PTEN is required for myelin and axonal integrity, not remyelination.
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DOI：
10.1002/ana.22090
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发表时间：
2010-11
影响因子：
11.2
通讯作者：
Rowitch, David H.
中科院分区：
文献类型：
--
作者：
Harrington, Emily P.;Zhao, Chao;Fancy, Stephen P. J.;Kaing, Sovann;Franklin, Robin J. M.;Rowitch, David H.
多发性硬化中髓鞘损伤的修复可能失败，导致慢性脱髓鞘、轴突缺失和疾病进展。作为由10号染色体上缺失的磷酸酶和张力蛋白同源物（PTEN;例如，PI-3激酶）增强轴突再生和少突胶质细胞成熟，我们研究了少突胶质细胞谱系中Pten功能丧失对髓鞘再生的潜在有益作用。我们在少突胶质细胞、Olig2-cre、Ptenfl/fl小鼠中用条件性失活PTEN表征了小鼠中的少突胶质细胞数量和髓鞘厚度。利用中枢神经系统脱髓鞘模型，将溶血素注射到脊髓白色物质中，我们进行了短期和长期损伤实验，并量化了髓鞘再生损伤中的少突胶质细胞成熟和髓鞘厚度。在发育过程中，我们观察到戏剧性的过度髓鞘化胼胝体和脊髓。然而，在白色物质损伤后，髓鞘修复没有明显改善。此外，我们观察到进行性髓鞘异常和大量的轴突变性的薄束突变动物，如超微结构和SMI-32，APP和Caspase 6的表达。这些研究表明慢性PTEN失活（并通过扩展，激活PI-3K信号传导）对髓鞘形成少突胶质细胞及其轴突靶点的不利影响。我们的结论是，Pten在少突胶质细胞的功能是需要调节髓鞘厚度和维护轴突的完整性。相比之下，Pten在髓鞘修复过程中是可有可无的，并且其失活不会带来可检测到的益处。
Repair of myelin injury in multiple sclerosis may fail resulting in chronic demyelination, axonal loss and disease progression. As cellular pathways regulated by Phosphatase and tensin homologue deleted on chromosome 10 (PTEN; e.g., PI-3Kinase) have been reported to enhance axon regeneration and oligodendrocyte maturation, we investigated potentially beneficial effects of Pten loss-of-function in the oligodendrocyte lineage on remyelination. We characterized oligodendrocyte numbers and myelin sheath thickness in mice with conditional inactivation of PTEN in oligodendrocytes, Olig2-cre, Ptenfl/fl mice. Utilizing a model of CNS demyelination, lysolecithin injection into the spinal cord white matter, we performed short and long-term lesioning experiments and quantified oligodendrocyte maturation and myelin sheath thickness in remyelinating lesions. During development, we observed dramatic hypermyelination in the corpus callosum and spinal cord. Following white matter injury, however, there was no detectable improvement in myelin repair. Moreover, we observed progressive myelin sheath abnormalities and massive axon degeneration in the fasciculus gracilis of mutant animals, as indicated by ultrastructure and expression of SMI-32, APP and Caspase 6. These studies indicate adverse effects of chronic PTEN inactivation (and by extension, activation PI-3K signaling) on myelinating oligodendrocytes and their axonal targets. We conclude that Pten function in oliogodendrocytes is required to regulate myelin thickness and preserve axon integrity. In contrast, Pten is dispensable during myelin repair and its inactivation confers not detectable benefit.
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影响因子：
16.2
作者：
Brinkmann, Bastian G.;Agarwal, Amit;Sereda, Michael W.;Garratt, Alistair N.;Mueller, Thomas;Wende, Hagen;Stassart, Ruth M.;Nawaz, Schanila;Humml, Christian;Velanac, Viktorija;Radyushkin, Konstantin;Goebbels, Sandra;Fischer, Tobias M.;Franklin, Robin J.;Lai, Cary;Ehrenreich, Hannelore;Birchmeier, Carmen;Schwab, Markus H.;Nave, Klaus Armin
通讯作者：
Nave, Klaus Armin
影响因子：
2.7
作者：
Furusho, Miki;Ono, Katsuhiko;Ikenaka, Kazuhiro
通讯作者：
Ikenaka, Kazuhiro
影响因子：
6.4
作者：
Billiards, Saraid S.;Haynes, Robin L.;Kinney, Hannah C.
通讯作者：
Kinney, Hannah C.
影响因子：
14.5
作者：
De Stefano, N;Matthews, PM;Arnold, DL
通讯作者：
Arnold, DL
影响因子：
6
作者：
Johnson, Trina A.;Tsutsui, Shigeki;Jirik, Frank R.
通讯作者：
Jirik, Frank R.