Polysialic acid-directed migration and differentiation of neural precursors are essential for mouse brain development
Polysialic acid-directed migration and differentiation of neural precursors are essential for mouse brain development
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DOI：
10.1128/mcb.00205-07
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发表时间：
2007-10-01
影响因子：
5.3
通讯作者：
Fukuda, Minoru
中科院分区：
文献类型：
--
作者：
Angata, Kiyohiko;Huckaby, Valerie;Fukuda, Minoru
聚唾液酸由两种聚唾液基转移酶ST8SiaII和ST8SiaIV合成，通过修饰神经细胞粘附分子（NCAM）在脑发育中起重要作用。目前尚不清楚聚唾液酸如何在不同的神经发育过程中起作用。在这里，我们制造了ST8SiaII和ST8SiaIV的小鼠双突变体，以确定聚唾液酸缺失对大脑发育的影响。与ncam缺陷、ST8SiaII缺陷或ST8SiaIV缺陷单突变小鼠相比，ST8SiaII和ST8SiaIV双突变小鼠在前脑解剖组织中表现出与凋亡细胞死亡相关的严重缺陷。在皮质发育过程中，聚唾液酸的缺失会影响神经前体的切向和径向迁移，导致神经元和胶质细胞的异常定位。在缺乏聚唾液酸的情况下，神经胶质细胞的分化在体内和体外都异常增加。与这些发现一致的是，多唾液酸缺乏小鼠表现出神经胶质细胞标志物胶质原纤维酸性蛋白的表达增加，而调节神经细胞迁移的转录因子Pax6的表达减少。这些结果表明，聚唾液酸调节了对大脑发育至关重要的神经前体的细胞迁移和分化。
Polysialic acid, which is synthesized by two polysialyltransferases, ST8SiaII and ST8SiaIV, plays an essential role in brain development by modifying the neural cell adhesion molecule (NCAM). It is currently unclear how polysialic acid functions in different processes of neural development. Here we generated mice doubly mutant in both ST8SiaII and ST8SiaIV to determine the effects of loss of polysialic acid on brain development. In contrast to NCAM-deficient, ST8SiaII-deficient, or ST8SiaIV-deficient single mutant mice, ST8SiaII and ST8SiaIV double mutants displayed severe defects in anatomical organization of the forebrain associated with apoptotic cell death. Loss of polysialic acid affected both tangential and radial migration of neural precursors during cortical development, resulting in aberrant positioning of neuronal and glial cells. Glial cell differentiation was aberrantly increased in vivo and in vitro in the absence of polysialic acid. Consistent with these findings, polysialic acid-deficient mice exhibited increased expression of the glial cell marker glial fibrillary acidic protein and a decrease in expression of Pax6, a transcription factor regulating neural cell migration. These results indicate that polysialic acid regulates cell migration and differentiation of neural precursors crucial for brain development.