Developmental abnormalities of myelin basic protein expression in fyn knock-out brain reveal a role of Fyn in posttranscriptional regulation
Developmental abnormalities of myelin basic protein expression in fyn knock-out brain reveal a role of Fyn in posttranscriptional regulation
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DOI：
10.1074/jbc.m405973200
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发表时间：
2005-01-07
影响因子：
4.8
通讯作者：
Feng, Y
中科院分区：
文献类型：
--
作者：
Lu, ZF;Ku, L;Feng, Y
Fyn蛋白酪氨酸激酶（PTK）是Src-PTK家族的一员，在中枢神经系统（CNS）髓鞘发育中起重要作用。缺乏Fyn活性导致少突胶质细胞前体（OPC）的形态发生缺陷和CNS髓鞘形成不足。然而，Fyn控制CNS髓鞘形成的分子机制仍然难以捉摸。在这里，我们表明，Fyn-PTK是显着上调，在早期OPC分化，集中在紧凑的髓鞘，并在髓鞘发育过程中下降。尽管在早期OPC分化过程中Fyn-PTK表达水平很高，但Fyn缺乏直到出生后第13天（P13）才影响编码髓鞘结构蛋白（包括髓鞘碱性蛋白（MBP））的mRNA的表达。然而，在髓鞘形成的最活跃时期（P13和P20），MBP mRNA的积累速率显著减弱。有趣的是，Fyn的缺乏导致优先减少的外显子-2含有MBP mRNA亚型来自选择性剪接，提供了第一个证据，Fyn是必需的转录后调节MBP。与这一想法一致，Fyn磷酸化选择性RNA结合蛋白QKI，这可能调节QKI结合和稳定MBP mRNA的活性。此外，Fyn缺乏对MBP亚型模式化产生相反的影响，与QKI缺乏相比。这些观察结果共同表明，Fyn在髓鞘形成过程中以MBP同种型优先的方式促进MBP加速表达中起着关键作用，QKI可能在Fyn下游相同的途径中起作用，以实现MBP mRNA的稳态。
Fyn protein-tyrosine kinase (PTK), a member of the Src-PTK family, is essential for myelin development in the central nervous system (CNS). The absence of Fyn activity results in defects in the morphogenesis of oligodendrocyte precursors (OPCs) and CNS hypomyelination. However, molecular mechanisms for Fyn to control CNS myelinogenesis remain elusive. Here we show that Fyn-PTK is significantly up-regulated in early OPC differentiation, concentrated in the compact myelin, and declines during myelin development. Despite the high levels of Fyn-PTK expression during early OPC differentiation, Fyn deficiency does not affect the expression of mRNAs that encode myelin structural proteins, including that for the myelin basic protein (MBP), until postnatal day 13 (P13). However, the accumulation rate of MBP mRNA is significantly attenuated during the most active period of myelinogenesis (P13 and P20). Interestingly, the absence of Fyn causes a preferential reduction of the exon-2 containing MBP mRNA isoforms derived from alternative splicing, providing the first evidence that Fyn is required for posttranscriptional regulation of MBP. Consistent with this idea, Fyn phosphorylates the selective RNA-binding protein QKI, which likely modulates the activity of QKI in binding and stabilizing the MBP mRNA. Furthermore, Fyn deficiency exerts an opposing influence on MBP isoform patterning in comparison to that by QKI deficiency. These observations collectively suggest that Fyn plays critical roles in promoting accelerated MBP expression during myelinogenesis in a MBP isoform-preferential manner, and QKI may act in the same pathway downstream of Fyn for MBP mRNA homeostasis.