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.
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