Down-regulation of polysialic acid is required for efficient myelin formation
Down-regulation of polysialic acid is required for efficient myelin formation
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DOI：
10.1074/jbc.m610797200
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发表时间：
2007-06-01
影响因子：
4.8
通讯作者：
Eckhardt, Matthias
中科院分区：
文献类型：
--
作者：
Fewou, Simon Ngamli;Ramakrishnan, Hariharasubramanian;Eckhardt, Matthias
少突胶质前体细胞通过聚唾液酸（PSA）的附着修饰神经细胞粘附分子（NCAM）。然而，在进一步分化为成熟的髓鞘少突胶质细胞后，少突胶质细胞前体细胞下调PSA合成。为了解决这种下调是否是髓鞘形成过程的必要前提，我们产生了在蛋白脂蛋白启动子控制下表达多唾液基转移酶ST8SiaIV的转基因小鼠。在这些小鼠中，出生后少突胶质细胞中PSA的下调被消除。大多数NCAM-120（少突胶质细胞中特有的NCAM亚型）在转基因小鼠出生后发育的所有阶段都携带PSA。多唾液化的NCAM-120与髓鞘碱性蛋白部分共定位，存在于纯化的髓鞘中。PSA-NCAM在少突胶质细胞中的永久表达导致转基因小鼠在髓鞘形成活跃期和成年动物的前脑髓磷脂含量降低。原位杂交显示前脑成熟少突胶质细胞数量明显减少。因此，在少突胶质细胞分化过程中，PSA的下调是成熟少突胶质细胞有效髓鞘形成的先决条件。此外，转基因小鼠髓磷脂表现出髓磷脂冗余和轴突变性等结构异常，表明PSA下调也是髓磷脂维持所必需的。
Oligodendrocyte precursor cells modify the neural cell adhesion molecule ( NCAM) by the attachment of polysialic acid ( PSA). Upon further differentiation into mature myelinating oligodendrocytes, however, oligodendrocyte precursor cells down-regulate PSA synthesis. In order to address the question of whether this down-regulation is a necessary prerequisite for the myelination process, transgenic mice expressing the polysialyltransferase ST8SiaIV under the control of the proteolipid protein promoter were generated. In these mice, postnatal down-regulation of PSA in oligodendrocytes was abolished. Most NCAM-120, the characteristic NCAM isoform in oligodendrocytes, carried PSA in the transgenic mice at all stages of postnatal development. Polysialylated NCAM-120 partially colocalized with myelin basic protein and was present in purified myelin. The permanent expression of PSA-NCAM in oligodendrocytes led to a reduced myelin content in the forebrains of transgenic mice during the period of active myelination and in the adult animal. In situ hybridizations indicated a significant decrease in the number of mature oligodendrocytes in the forebrain. Thus, down-regulation of PSA during oligodendrocyte differentiation is a prerequisite for efficient myelination by mature oligodendrocytes. Furthermore, myelin of transgenic mice exhibited structural abnormalities like redundant myelin and axonal degeneration, indicating that the down-regulation of PSA is also necessary for myelin maintenance.