Neural RNA-Binding Protein Musashi1 Controls Midline Crossing of Precerebellar Neurons through Posttranscriptional Regulation of Robo3/Rig-1 Expression
Neural RNA-Binding Protein Musashi1 Controls Midline Crossing of Precerebellar Neurons through Posttranscriptional Regulation of Robo3/Rig-1 Expression
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DOI：
10.1016/j.neuron.2010.07.005
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发表时间：
2010-08-12
期刊：
影响因子：
16.2
通讯作者：
Okano, Hideyuki
中科院分区：
文献类型：
--
作者：
Kuwako, Ken-ichiro;Kakumoto, Kyoko;Okano, Hideyuki
精确调控的时空基因表达对于神经回路的建立至关重要。与越来越多的证据表明轴突引导信号和受体的转录调控相反，转录后调控在轴突引导中的作用，特别是在体内，仍然缺乏特征。在这里，我们证明了在轴突中线交叉中起关键作用的缝隙受体Robo3/RIG-1的表达受神经RNA结合蛋白Musashi1(Msi1)的调节。MSI1通过RNA识别基序与Robo3mRNA结合，在不影响其mRNA水平的情况下增加Robo3的蛋白质水平。在Msi1缺陷的小脑前神经元中，Robo3蛋白而不是其mRNA显著减少。此外，与Robo3基因缺陷小鼠类似，Msi1基因缺陷小鼠小脑前神经元的轴突中线交叉和神经元迁移严重受损。综上所述，这些发现表明，Msi1介导的Robo3转录后调控控制着小脑前神经元的中线交叉。
Precisely regulated spatiotemporal gene expression is essential for the establishment of neural circuits. In contrast to the increasing evidence for transcriptional regulation of axon guidance cues and receptors, the role of posttranscriptional regulation in axon guidance, especially in vivo, remains poorly characterized. Here, we demonstrate that the expression of Slit receptor Robo3/Rig-1, which plays crucial roles in axonal midline crossing, is regulated by a neural RNA-binding protein Musashi1 (Msi1). Msi1 binds to Robo3 mRNA through RNA recognition motifs and increases the protein level of Robo3 without affecting its mRNA level. In Msi1-deficient precerebellar neurons, Robo3 protein, but not its mRNA, is dramatically reduced. Moreover, similar to defects in Robo3-deficient mice, axonal midline crossing and neuronal migration of precerebellar neurons are severely impaired in Msi1-deficient mice. Together, these findings indicate that Msi1-mediated posttranscriptional regulation of Robo3 controls midline crossing of precerebellar neurons.