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至关重要。髓鞘形成和修复的失败导致许多神经系统疾病。我们的长期目标是阐明控制髓鞘生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必要先决条件。本研究旨在阐明选择性RNA结合蛋白OKI在中枢神经系统（CMS）中促进少突胶质细胞和髓鞘发育的功能。OKI是一个关键的球员，控制mRNA的稳态和亚细胞定位响应发育信号。在quakingviable（qvod）突变小鼠中，少突胶质细胞中OKI表达减少导致CMS髓鞘形成障碍的严重缺陷，这可以通过我们在少突胶质细胞谱系中特异性表达QKI的转基因小鼠来挽救。尽管QKI在髓鞘形成中的功能要求，但QKI如何促进髓鞘形成仍然是难以捉摸的。我们最近的初步研究表明，RNAi介导的QKI敲低减弱了少突胶质细胞的分化/成熟，这表明QKI在实际髓鞘形成之前在少突胶质细胞的发育中也起着重要作用。我们进一步表明，QKI选择性地相互作用，在少突胶质细胞祖细胞增殖/分化和髓鞘合成不同的mRNA种类。此外，Fyn（一种对少突胶质细胞和髓鞘发育至关重要的Src家族激酶）对QKI的酪氨酸磷酸化调节QKI的RNA结合活性。因此，我们假设QKI促进髓鞘形成，通过增强少突胶质细胞分化和髓鞘生产，通过控制稳定性和亚细胞定位的不同的mRNA靶响应发育调节酪氨酸磷酸化。我们提出以下目的来验证这一假设：1）描述QKI如何控制少突胶质细胞祖细胞的增殖/分化; 2）阐明QKI促进髓鞘合成和拯救髓鞘形成障碍的分子机制; 3）确定在少突胶质细胞发育过程中，QKI的酪氨酸磷酸化是否以及如何被调节以控制其配体mRNA的细胞行为。这些问题的答案将显着推进我们对少突胶质细胞和髓鞘发育的基本机制的认识，这可能最终有助于开发新的策略，以增强髓鞘形成对髓鞘疾病。

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.