Transgenic overexpression of polysialyltransferase ST8SiaIV under the control of a neuron-specific promoter does not affect brain development but impairs exploratory behavior
Transgenic overexpression of polysialyltransferase ST8SiaIV under the control of a neuron-specific promoter does not affect brain development but impairs exploratory behavior
复制标题
DOI：
10.1093/glycob/cwz040
复制
发表时间：
2019-09-01
期刊：
影响因子：
4.3
通讯作者：
Eckhardt, Matthias
中科院分区：
文献类型：
--
作者：
Fewou, Simon Ngamli;Roeckle, Iris;Eckhardt, Matthias
大量文献已经证明，神经细胞粘附分子（NCAM）的聚唾液酸（polySia）修饰是脑发育、维持和可塑性期间细胞相互作用的关键调节剂。为了适当地实现这些功能，必须仔细控制polySia浓度。这是通过调节两种聚Sia合成酶ST 8 SiaII和ST 8 SiaIV的表达来实现的。从这个角度来看，我们和其他人已经证明，在少突胶质细胞分化过程中下调ST 8 SiaIV是有效的髓鞘形成和维持的先决条件。在这里，我们解决了神经元中polySia下调的预防是否会影响大脑，特别是髓鞘发育和功能的问题。为此，我们开发了在神经元中过表达多聚唾液酸转移酶ST 8 SiaIV的转基因（tg）小鼠品系。ST 8 SiaIV的tg表达阻止了出生后polySia的下调，并且成年tg小鼠前脑和脑干中的大多数polySia与NCAM-140和NCAM-180同种型相关。脑结构检查显示轴突和髓鞘无明显异常。此外，超微结构和蛋白质印迹分析表明髓鞘发育正常。然而，行为研究显示，减少饲养活动，探索行为的措施，而运动活动参数没有受到影响的tg小鼠。总而言之，这些结果表明，神经元中持续存在的polySia对大脑结构、髓鞘形成和髓鞘维持没有重大影响，但会引起轻微的行为变化。
A large body of the literature has demonstrated that the polysialic acid (polySia) modification of the neural cell adhesion molecule (NCAM) is a key regulator of cellular interactions during brain development, maintenance and plasticity. To properly fulfill these functions, polySia concentration has to be carefully controlled. This is done by the regulation of the expression of the two polySia-synthesizing enzymes ST8SiaII and ST8SiaIV. From this point of view we and others have demonstrated that downregulation of ST8SiaIV during oligodendrocyte differentiation is a prerequisite for efficient myelin formation and maintenance. Here, we addressed the question whether the prevention of polySia downregulation in neurons affects brain and particularly myelin development and functioning. For this purpose, we developed transgenic (tg) mouse lines overexpressing the polysialyltransferase ST8SiaIV in neurons. tg expression of ST8SiaIV prevented the postnatal downregulation of polySia, and most of the polySias in the forebrain and brain stem of adult tg mice were associated with NCAM-140 and NCAM-180 isoforms. Structural examination of the brain revealed no overt abnormalities of axons and myelin. In addition, ultrastructural and western blot analyses indicated normal myelin development. However, behavioral studies revealed reduced rearing activity, a measure for exploratory behavior, while parameters of motor activity were not affected in tg mice. Taken together, these results suggest that a persisting presence of polySia in neurons has no major effect on brain structure, myelination and myelin maintenance, but causes mild behavioral changes.