m6A Modifications Play Crucial Roles in Glial Cell Development and Brain Tumorigenesis

Abstract

RNA methylation is a reversible post-transcriptional modification to RNA and has a significant impact on numerous biological processes. N ⁶-methyladenosine (m⁶A) is known as one of the most common types of eukaryotic mRNA methylation modifications, and exists in a wide variety of organisms, including viruses, yeast, plants, mice, and humans. Widespread and dynamic m⁶A methylation is identified in distinct developmental stages in the brain, and controls development of neural stem cells and their differentiation into neurons, glial cells such as oligodendrocytes and astrocytes. Here we summarize recent advances in our understanding of RNA methylation regulation in brain development, neurogenesis, gliogenesis, and its dysregulation in brain tumors. This review will highlight biological roles of RNA methylation in development and function of neurons and glial cells, and provide insights into brain tumor formation, and diagnostic and treatment strategies.

Keywords: N6-methyladenosine (m6A); brain development; brain tumor; glial cell; glioma; neural stem cell.

Figure 1

Scheme of m⁶A modifications. The writers, erasers, and readers of N6-methyladenosine (m⁶A). The m⁶A writer complex, which comprises the core methyltransferase-like protein 3 (METTL3) and its adaptors, is located in the nucleus. m⁶A demethylation is executed by two demethylases FTO and ALKBH5. The m⁶A erasers also are localized in the nucleus. In the nucleus, m⁶A can bind specific nuclear reader proteins such as YTHDC1 and HNRNPA2/B1, which may affect RNA splicing and mRNA export. Upon mRNA being exported to the cytoplasm, m⁶A binds to specific reader proteins, which affects stability, translation and/or localization of mRNAs. In the cytoplasm, translation of m⁶A modified mRNAs is mediated by the m⁶A readers YTHDF1, YTHDF3, and YTHDC2, the eukaryotic translation initiation factor eIF3, and METTL3. YTHDF2 and YTHDF3 regulate degradation of m⁶A modified mRNAs, while the insulin-like growth factor 2 mRNA-binding proteins (IGF2BPs) enhances stability m⁶A modified mRNAs.

Figure 2

The biological impact of m⁶A modifications in mouse brain development. m⁶A modifications play a key role throughout brain development during mouse embryonic and postnatal stages. Mettl14 conditional knockout mouse (cKO) in the mouse embryonic brain causes prolonged cell cycle in cortical radial glial cells, results in delayed neurogenesis and gliogenesis, compared to wild type (WT) mice. Conditional depletion of Ythdf2 in mice causes decreased self-renewal of neural stem/progenitor cells (NSPCs) and defects in spatiotemporal generation of neurons in the embryonic cortex. Knocking out Mettl3 in the mouse embryonic brain causes cerebellar hypoplasia. Ectopic expression of Mettl3 leads to a disorganized laminal structure of both Purkinje cells and glial cells. Key developmental genes such as Atoh1 and Cxcr4 are abnormally upregulated due to the extended mRNA half-lives induced by m⁶A depletion.

Figure 3

Functions of m⁶A modifications in brain tumors. N6-methyladenosine (m⁶A) modifications play a crucial role in brain tumorigenesis. Inadequate or dysregulated expression of writers, erasers, and readers of m⁶A is associated with brain tumor formation.