Role of QKI in oligodendroglia and myelin development

描述(由申请人提供)：髓鞘形成对神经系统的发育和功能是必不可少的。髓鞘形成和修复失败会导致许多神经系统疾病。我们的长期目标是阐明控制髓鞘形成的分子和细胞机制，这是开发针对髓鞘疾病的新治疗策略的基本前提。本研究旨在阐明选择性RNA结合蛋白OKI在促进中枢神经系统(CMS)少突胶质细胞和髓鞘发育中的作用。Oki是一个关键的参与者，它控制着mRNA的动态平衡和亚细胞定位，以响应发育信号。少突胶质细胞中OKI表达的减少导致可突变(QKV)突变小鼠的CMS髓鞘生成严重缺陷，这可以通过我们的转基因小鼠在少突胶质细胞系中特异性表达QKI来挽救。尽管QKI在髓鞘形成中有功能要求，但QKI如何促进髓鞘形成仍不清楚。我们最近的初步研究表明，RNAi介导的QKI基因敲除减弱了少突胶质细胞的分化/成熟，这表明在真正的髓鞘形成之前，QKI也在少突胶质细胞的发育中发挥重要作用。我们进一步表明，在少突胶质前体细胞增殖/分化和髓鞘合成过程中，QKI选择性地与不同的信使核糖核酸相互作用。此外，对少突胶质细胞和髓鞘发育至关重要的Src家族激酶Fyn对QKI的酪氨酸磷酸化作用调节QKI的RNA结合活性。因此，我们假设QKI通过促进少突胶质细胞分化和髓鞘生成来促进髓鞘形成，这是通过控制发育调节的酪氨酸磷酸化反应中不同mRNA靶点的稳定性和亚细胞定位来实现的。1)阐明QKI如何控制少突胶质前体细胞的增殖/分化；2)阐明QKI促进髓鞘合成和挽救QKV髓鞘障碍的分子机制；3)确定QKI的酪氨酸磷酸化是否以及如何被调控以控制其配体mRNAs在少突胶质细胞发育过程中的细胞行为。对这些问题的回答将极大地促进我们对支配少突胶质细胞和髓鞘发育的基本机制的了解，这最终可能有助于开发新的策略来增强髓鞘形成以对抗髓鞘疾病。

DESCRIPTION (provided by applicant): Myelination is essential for the development and function of the nervous system. Failures in myelination and repair result in many neurological diseases. Our long-term goal is to elucidate molecular and cellular mechanisms that control myelinogenesis, which is an essential prerequisite for developing novel therapeutic strategies against myelin disorders. This proposal focuses on elucidating the function of the selective RNA- binding protein OKI in promoting oligodendroglia and myelin development in the central nervous system (CMS). OKI is a pivotal player that controls mRNA homeostasis and subcellular localization in response to developmental signals. Diminished OKI expression in oligodendrocytes leads to severe defects in CMS dysmyelinogenesis in the quakingviable (qkv) mutant mice, which can be rescued by our transgenic mice that express QKI specifically in the oligodendroglia lineage. Despite the functional requirement of QKI in myelination, how QKI promotes myelinogenesis remains elusive. Our recent preliminary studies revealed that RNAi-mediated QKI knockdown attenuates oligodendroglia differentiation/maturation, suggesting that QKI also plays essential roles in oligodendroglia development before actual myelin formation. We further show that QKI selectively interacts with distinct mRNA species during oligodendroglia progenitor proliferation/differentiation and myelin synthesis. Moreover, tyrosine phosphorylation of QKI by Fyn, a Src family kinase critical for oligodendroglia and myelin development, modulates the RNA-binding activity of QKI. Hence, we hypothesize that QKI promotes myelinogenesis by enhancing oligodendroglia differentiation and myelin production via controlling the stability and subcellular localization of distinct mRNA targets in response to developmentally regulated tyrosine phosphorylation. We propose the following aims to test this hypothesis: 1) To delineate how QKI controls proliferation/differentiation of oligodendroglia progenitors; 2) To elucidate molecular mechanisms for QKI to promote myelin synthesis and rescue qkv dysmyelination; 3) To determine whether and how tyrosine phosphorylation of QKI is regulated to control the cellular behavior of its ligand mRNAs during oligodendroglia development. Answers to these questions will significantly advance our knowledge on the fundamental mechanisms that govern oligodendroglia and myelin development, which may ultimately help to develop novel strategies to enhance myelination against myelin disorders.