A LewisX Glycoprotein Screen Identifies the Low Density Lipoprotein Receptor-related Protein 1 (LRP1) as a Modulator of Oligodendrogenesis in Mice
A LewisX Glycoprotein Screen Identifies the Low Density Lipoprotein Receptor-related Protein 1 (LRP1) as a Modulator of Oligodendrogenesis in Mice
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DOI：
10.1074/jbc.m112.419812
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发表时间：
2013-06-07
影响因子：
4.8
通讯作者：
Faissner, Andreas
中科院分区：
文献类型：
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作者：
Hennen, Eva;Safina, Dina;Faissner, Andreas
在发育中和成年的中枢神经系统中，多能神经干细胞存在于不同的生态位中。特定的碳水化合物和糖蛋白在这些生态位微环境中表达，它们是干细胞维持和分化命运的重要调节因子。 LewisX (LeX) 也称为阶段特异性胚胎抗原 1 或 CD15，是在发育中和成年 CNS 的生态位微环境中表达的明确碳水化合物部分。 LeX-聚糖参与干细胞增殖、迁移和干细胞性。一些LeX载体蛋白是已知的，但迄今为止尚未对体内LeX糖基化的靶标进行系统分析。使用 LeX 糖基化作为生物标志物，我们旨在发现与中枢神经系统发育具有潜在功能相关性的新糖蛋白。通过免疫亲和层析，我们富集了胚胎和出生后小鼠大脑中的 LeX 糖蛋白，并使用一维 nLC-ESI-MS/MS 进行鉴定。我们可以验证磷酸聚糖、腱蛋白-C 和 L1-CAM 作为体内存在的主要 LeX 载体蛋白。此外，我们鉴定了LDL受体家族成员LRP1作为小鼠神经干细胞表达的新LeX载体蛋白。令人惊讶的是，人们对 LRP1 对神经干细胞的功能知之甚少。因此，我们通过 Cre 介导的重组产生了 Lrp1 敲除神经干细胞，并研究了它们的特性。在这里，我们提供了第一个证据，证明 LRP1 对于神经干细胞向少突胶质细胞的分化是必需的。然而，该功能独立于 LeX 糖基化。
In the developing and adult CNS multipotent neural stem cells reside in distinct niches. Specific carbohydrates and glycoproteins are expressed in these niche microenvironments which are important regulators of stem cell maintenance and differentiation fate. LewisX (LeX), also known as stage-specific embryonic antigen-1 or CD15, is a defined carbohydrate moiety expressed in niche microenvironments of the developing and adult CNS. LeX-glycans are involved in stem cell proliferation, migration, and stemness. A few LeX carrier proteins are known, but a systematic analysis of the targets of LeX glycosylation in vivo has not been performed so far. Using LeX glycosylation as a biomarker we aimed to discover new glycoproteins with a potential functional relevance for CNS development. By immunoaffinity chromatography we enriched LeX glycoproteins from embryonic and postnatal mouse brains and used one-dimensional nLC-ESI-MS/MS for their identification. We could validate phosphacan, tenascin-C, and L1-CAM as major LeX carrier proteins present in vivo. Furthermore, we identified LRP1, a member of theLDLreceptor family, as a new LeX carrier protein expressed by mouse neural stem cells. Surprisingly, little is known about LRP1 function for neural stem cells. Thus, we generated Lrp1 knock-out neural stem cells by Cre-mediated recombination and investigated their properties. Here, we provide first evidence that LRP1 is necessary for the differentiation of neural stem cells toward oligodendrocytes. However, this function is independent of LeX glycosylation.