Regulatory Mechanisms that Mediate Tenascin C-Dependent Inhibition of Oligodendrocyte Precursor Differentiation
Regulatory Mechanisms that Mediate Tenascin C-Dependent Inhibition of Oligodendrocyte Precursor Differentiation
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DOI：
10.1523/jneurosci.4957-09.2010
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发表时间：
2010-09-15
影响因子：
5.3
通讯作者：
Faissner, Andreas
中科院分区：
文献类型：
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作者：
Czopka, Tim;von Holst, Alexander;Faissner, Andreas
在这里，我们提出了抑制少突胶质细胞前体细胞（OPC）分化的机制，神经细胞外基质（ECM）的生物学功能。少突胶质细胞的分化是由一组复杂的刺激所协调的。在本研究中，我们研究了ECM糖蛋白腱生蛋白C（Tnc）引起的信号通路。Tnc底物抑制髓鞘碱性蛋白（MBP）表达培养的大鼠少突胶质细胞，而且，相反，我们发现，出现的MBP表达的Tnc缺陷小鼠的前脑加速。从机制上讲，Tnc干扰Akt的磷酸化，从而降低MBP的表达。在细胞表面，Tnc与少突胶质细胞膜中的脂筏以及细胞粘附分子contactin（Cntn 1）和Src家族激酶（SFK）Fyn结合。通过小干扰RNA（siRNA）消耗OPCs中的Cntn1，废除了少突胶质细胞分化的Tnc依赖性抑制，而Tnc暴露阻碍了Cntn1对酪氨酸激酶Fyn的激活。伴随少突胶质细胞分化，Tnc拮抗信号衔接子和RNA结合分子Sam68的表达。siRNA介导的Sam68的敲低或过表达分别延迟或加速少突胶质细胞分化。SFK抑制剂PP2对少突胶质细胞分化的抑制可以通过Sam68过表达来挽救，这可能表明Sam68在Fyn下游的调节作用。因此，我们的研究揭示了第一个信号转导通路的基础，Tnc诱导，ECM依赖性的维护未成熟状态的OPCs。
Here, we present mechanisms for the inhibition of oligodendendrocyte precursor cell (OPC) differentiation, a biological function of neural extracellular matrix (ECM). The differentiation of oligodendrocytes is orchestrated by a complex set of stimuli. In the present study, we investigated the signaling pathway elicited by the ECM glycoprotein tenascin C (Tnc). Tnc substrates inhibit myelin basic protein (MBP) expression of cultured rat oligodendrocytes, and, conversely, we found that the emergence of MBP expression is accelerated in forebrains of Tnc-deficient mice. Mechanistically, Tnc interfered with phosphorylation of Akt, which in turn reduced MBP expression. At the cell surface, Tnc associates with lipid rafts in oligodendrocyte membranes, together with the cell adhesion molecule contactin (Cntn1) and the Src family kinase (SFK) Fyn. Depletion of Cntn1 in OPCs by small interfering RNAs (siRNAs) abolished the Tnc-dependent inhibition of oligodendrocyte differentiation, while Tnc exposure impeded the activation of the tyrosine kinase Fyn by Cntn1. Concomitant with oligodendrocyte differentiation, Tnc antagonized the expression of the signaling adaptor and RNA-binding molecule Sam68. siRNA-mediated knockdown or overexpression of Sam68 delayed or accelerated oligodendrocyte differentiation, respectively. Inhibition of oligodendrocyte differentiation with the SFK inhibitor PP2 could be rescued by Sam68 overexpression, which may indicate a regulatory role for Sam68 downstream of Fyn. Our study therefore uncovers the first signaling pathways that underlie Tnc-induced, ECM-dependent maintenance of the immature state of OPCs.