Impact of the polysialyltransferases ST8Siall and ST8SiaIV on polysialic acid synthesis during postnatal mouse brain development
Impact of the polysialyltransferases ST8Siall and ST8SiaIV on polysialic acid synthesis during postnatal mouse brain development
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DOI：
10.1074/jbc.m708463200
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发表时间：
2008-01-18
影响因子：
4.8
通讯作者：
Muehlenhoff, Martina
中科院分区：
文献类型：
--
作者：
Oltmann-Norden, Imke;Galuska, Sebastian P.;Muehlenhoff, Martina
聚唾液酸（polySia）是神经细胞粘附分子（NCAM）的翻译后修饰，是NCAM介导功能的关键调节剂，对正常的大脑发育、出生后生长和生存至关重要。两种聚硅转移酶ST8SiaII和ST8SiaIV介导聚硅的生物合成。为了分析每种酶在出生后大脑发育过程中的影响，我们使用出生后1至21天的10个时间点和成年小鼠的全脑裂解液，监测了野生型、ST8SiaII-和st8siaiv缺陷小鼠NCAM多唾液化的发育变化。在野生型和ST8SiaIV- null脑中，直到第9天，多sia生物合成与脑重量的快速增加保持同步，几乎所有的NCAM都被多唾液化。此后，polySia在1周内下降约70%，并首次出现无polySia的NCAM-140和NCAM-180。在st8siai -null脑中，polySia在出生后立即下降，导致第9天的polySia减少60%，并过早出现无polySia的NCAM。多唾液基转移酶缺乏没有改变NCAM的表达水平或亚型模式。在所有三种基因型中，NCAM-140和NCAM- 180在第1天至第21天以恒定水平表达，并提供主要的多sia受体。相比之下，NCAM- 120在第5天首次出现，随后出现与polySia减少相反的强烈上调。总之，我们提供了一个全面的定量分析在发育变化的polySia水平，NCAM多唾液酰化状态和多唾液酰转移酶转录水平，并表明ST8SiaII在出生后大脑发育中的主导作用仅限于前15天。
Polysialic acid (polySia), a post-translational modification of the neural cell adhesion molecule (NCAM), is the key regulator of NCAM-mediated functions and crucial for normal brain development, postnatal growth, and survival. Two polysialyl-transferases, ST8SiaII and ST8SiaIV, mediate polySia biosynthesis. To dissect the impact of each enzyme during postnatal brain development, we monitored the developmental changes in NCAM polysialylation in wild-type, ST8SiaII-, and ST8SiaIV-deficient mice using whole brain lysates obtained at 10 time points from postnatal days 1 to 21 and from adult mice. In wildtype and ST8SiaIV- null brain, polySia biosynthesis kept pace with the rapid increase in brain weight until day 9, and nearly all NCAM was polysialylated. Thereafter, polySia dropped by similar to 70% within 1 week, accompanied by the first occurrence of polySia-free NCAM-140 and NCAM-180. In ST8SiaII-null brain, polySia declined immediately after birth, leading to 60% less polySia at day 9 combined with the untimely appearance of polySia-free NCAM. Polysialyltransferase deficiency did not alter NCAM expression level or isoform pattern. In all three genotypes, NCAM-140 and NCAM- 180 were expressed at constant levels from days 1 to 21 and provided the major polySia acceptors. By contrast, NCAM- 120 first appeared at day 5, followed by a strong up- regulation inverse to the decrease in polySia. Together, we provide a comprehensive quantitative analysis of the developmental changes in polySia level, NCAM polysialylation status, and polysialyltransferase transcript levels and show that the predominant role of ST8SiaII during postnatal brain development is restricted to the first 15 days.