Myelination of Neuronal Cell Bodies when Myelin Supply Exceeds Axonal Demand.
Myelination of Neuronal Cell Bodies when Myelin Supply Exceeds Axonal Demand.
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DOI：
10.1016/j.cub.2018.02.068
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发表时间：
2018-04-23
期刊：
影响因子：
--
通讯作者：
Lyons DA
中科院分区：
文献类型：
--
作者：
Almeida RG;Pan S;Cole KLH;Williamson JM;Early JJ;Czopka T;Klingseisen A;Chan JR;Lyons DA
髓鞘的正确靶向对于神经系统的形成和功能至关重要。CNS中的少突胶质细胞使一些轴突髓鞘化，但不使其它轴突髓鞘化，并且不使包括细胞体和树突的结构髓鞘化。最近的研究表明，外部信号，如神经元活动和细胞粘附分子，可以偏向髓鞘形成的一些轴突和远离细胞体和树突，表明在体内，神经元和轴突的线索调节髓鞘靶向。然而，在体外，少突胶质细胞具有髓鞘形成的内在倾向，并且可以混杂地包裹类似神经元突起或细胞体的惰性合成结构。目前治疗脱髓鞘疾病的治疗目标是极大地促进少突胶质细胞的发生;因此，重要的是测试外源性信号如何准确地调节体内少突胶质细胞的髓鞘形成的内在程序。在这里，我们测试的假设，神经元调节髓鞘形成有足够的严格性，始终确保正确的目标。然而，令人惊讶的是，我们发现，髓磷脂靶向在体内是不是很严格，并且mistargeting容易发生时，少突胶质细胞和髓磷脂供应超过轴突的需求。我们发现，髓鞘是错误的神经元细胞体在斑马鱼突变体与较少的轴突和独立的药物治疗的斑马鱼少突胶质细胞增多。此外，通过增加斑马鱼和小鼠中少突胶质细胞的髓鞘产生，我们发现过量的髓鞘也不适当地靶向细胞体。我们的研究结果表明，平衡少突胶质细胞内在的髓鞘供应与轴突需求的程序是必不可少的正确的髓磷脂靶向在体内，并强调潜在的负债，强烈促进少突胶质细胞的发生。轴突和髓鞘产生之间的平衡调节其体内靶向过量的髓鞘被错误地引导到细胞体正常发育期间的错误引导水平较低，但不是零，对髓鞘促进疗法的潜在影响Almeida等人。发现中枢神经系统中轴突需求和髓鞘产生之间的平衡调节髓鞘靶向。在发育中的中枢神经系统中，当正常的靶轴突减少，少突胶质细胞数量增加，或每少突胶质细胞的髓鞘产生增加时，髓鞘被错误地定位到细胞体，包括神经元的细胞体。
The correct targeting of myelin is essential for nervous system formation and function. Oligodendrocytes in the CNS myelinate some axons, but not others, and do not myelinate structures including cell bodies and dendrites. Recent studies indicate that extrinsic signals, such as neuronal activity and cell adhesion molecules, can bias myelination toward some axons and away from cell bodies and dendrites, indicating that, in vivo, neuronal and axonal cues regulate myelin targeting. In vitro, however, oligodendrocytes have an intrinsic propensity to myelinate and can promiscuously wrap inert synthetic structures resembling neuronal processes or cell bodies. A current therapeutic goal for the treatment of demyelinating diseases is to greatly promote oligodendrogenesis; thus, it is important to test how accurately extrinsic signals regulate the oligodendrocyte’s intrinsic program of myelination in vivo. Here, we test the hypothesis that neurons regulate myelination with sufficient stringency to always ensure correct targeting. Surprisingly, however, we find that myelin targeting in vivo is not very stringent and that mistargeting occurs readily when oligodendrocyte and myelin supply exceed axonal demand. We find that myelin is mistargeted to neuronal cell bodies in zebrafish mutants with fewer axons and independently in drug-treated zebrafish with increased oligodendrogenesis. Additionally, by increasing myelin production of oligodendrocytes in zebrafish and mice, we find that excess myelin is also inappropriately targeted to cell bodies. Our results suggest that balancing oligodendrocyte-intrinsic programs of myelin supply with axonal demand is essential for correct myelin targeting in vivo and highlight potential liabilities of strongly promoting oligodendrogenesis. Balance between axons and myelin production regulates its targeting in vivo Excess myelin is mistargeted to cell bodies Low, but not zero, level of mistargeting during normal development Potential implications for myelin-promoting therapies Almeida et al. find that the balance between axon demand and myelin production in the CNS regulates myelin targeting. In the developing CNS, when normal target axons are reduced, oligodendrocyte number increased, or myelin production per oligodendrocyte increased, myelin is mistargeted to cell bodies, including those of neurons.
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影响因子：
4.5
作者：
Ma, Ming;Jiang, Yun-Jin
通讯作者：
Jiang, Yun-Jin
影响因子：
30.8
作者：
Lappe-Siefke, C;Goebbels, S;Nave, KA
通讯作者：
Nave, KA
影响因子：
1.5
作者：
Lesche, R;Groszer, M;Wu, H
通讯作者：
Wu, H
神经元活动会影响体内髓鞘形成的轴突选择。
影响因子：
25
作者：
Hines, Jacob H.;Ravanelli, Andrew M.;Schwindt, Rani;Scott, Ethan K.;Appel, Bruce
通讯作者：
Appel, Bruce
影响因子：
2.5
作者：
KIMMEL, CB;BALLARD, WW;SCHILLING, TF
通讯作者：
SCHILLING, TF