The Role of m6A mRNA Methylation in Oligodendrocyte Development, CNS Myelination, and Remyelination /

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Bibliographic Details
Author / Creator:Xu, Huan, author.
Imprint:Ann Arbor : ProQuest Dissertations & Theses, 2021
Description:1 electronic resource (163 pages)
Format: E-Resource Dissertations
Local Note:School code: 0330
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Other authors / contributors:University of Chicago. degree granting institution.
Notes:Advisors: Popko, Brian Committee members: Zhuang, Xiaoxi; Gomez, Christopher; Pan, Tao.
Dissertations Abstracts International, Volume: 83-04, Section: B.
Summary:Oligodendrocytes are the myelin-forming cells in the central nervous system (CNS). Myelin is a multilayered membrane sheath structure that surrounds neuronal cell axons. Oligodendrocyte lineage cells and myelin are important for various CNS functions, such as electrical signal propagation and axonal metabolic support. Recent studies revealed oligodendrocyte lineage cells and myelin also play important roles in motor skill learning, memory and the aging process. Inherited and acquired myelination deficits such as leukodystrophies and multiple sclerosis result in severe neurological dysfunctions. At present, molecular mechanisms controlling oligodendrocyte differentiation and myelination are not comprehensively understood. Recent evidence has shown that RNA modification is a dynamic and reversible process, which adds a new layer of understanding to epigenetic regulation in biological processes. N6-methyladenosine (m⁶A), the most abundant internal modification site in eukaryotic messenger RNA (mRNA), is the first example of reversible RNA methylation. The conservative enrichment of m⁶A in stop codons, 3'-untranslated regions, and long internal exons in mice and humans suggest its fundamental importance in RNA biology. Discovery of m6A methyltransferase protein "writers," demethylase protein "erasers," and "readers" suggests their dynamic regulatory roles in reversible RNA modification. Many in vitro and in vivo studies have shown that reversible methylation of mRNA is essential for cell survival and cell differentiation. Compared to DNA and protein methylation, RNA modification has the potential to have rapid influence on mRNA metabolism and gene expression, and thereby contribute to rapid cellular responses to cellular and environmental cues. In the CNS, studies have found m⁶A mRNA methylation is critical for embryonic neruogenesis and neural repair. In addition, m⁶A mRNA methylation plays a regulatory role in various CNS functions such as learning and memory. As a glia population, oligodendrocyts share the same embryonic stem cell origin with neuorns, and actively interact with neurons to perform CNS functions. Therefore, it is highly important to understand whether m⁶A mRNA methylation plays a role in regulating oligodendrocytes lineage progression and function. This thesis will focus on understanding the potential role that m⁶A mRNA regulation plays in oligodendrocyte development, CNS myelination, and remyelination. Chapter 1 will provide an overview of the current knowledge of molecular mechanisms regulating oligodendrocyte lineage progression. Chapter 2 will describe our discovery of m⁶A mRNA modification mechanism in regulating oligodendrocyte lineage development and the myelination process. In mouse models that specifically inactivate an essential m⁶A writer component, METTL14, we found an abnormal myelination process and disrupted oligodendrocyte differentiation. We also discovered that Mettl14 deletion in oligodendrocyte lineage cells causes aberrant splicing of myriad RNA transcripts and disruption of gene expression, including an essential paranodal component neurofascin 155 (NF155). Chapter 3 will introduce the findings of m⁶A mRNA modification in the remyelination process in adult animals. We found that Mettl14 deletion in oligodendrocyte precursor cells (OPCs) prevents proper remyelination after the demyelination event. Chapter 4 will discuss how we can further enhance our understandings based on the findings in chapters 2 and 3, in order to gain a complete mechanistic picture of oligodendrocyte biology and promote therapeutic discoveries for myelin diseases.