# Reversible mRNA methylation in oligodendrocyte development and CNS myelination

> **NIH NIH R01** · NORTHWESTERN UNIVERSITY · 2021 · $349,636

## Abstract

Abstract
Myelin is essential for normal nervous system function in higher vertebrates, and recent data suggest that
myelin remodeling is critical for motor learning. Moreover, CNS myelin sheath and the oligodendrocytes
responsible for its synthesis are the targets of a number of neurological conditions, including genetic (e.g.
leukodystrophies) and acquired (e.g. multiple sclerosis) disorders. Therefore, it is critically important that we
gain a complete understanding of the pathways and mechanisms that regulate oligodendrocyte development
and myelin formation. Here, we propose to explore the epigenetic regulation of oligodendrocyte development,
function and response to environmental changes. Chromatin remodeling by histone deacetylases, DNA
methylation and gene silencing by non-coding RNAs are epigenetic mechanisms that have already been
shown to play a critical role in CNS myelination. In the studies described here the role that the reversible
methylation of RNA plays in oligodendrocyte lineage cells will be examined. Recently, N6-methyladenosine
(m6A) was shown to be the first example of reversible RNA methylation. Protein “writers”, “erasers” and
“readers” of this RNA mark have been discovered, strongly suggesting that these dynamic RNA modifications
play a regulatory role. Readers have been shown to influence the stability, translation, splicing and intracellular
localization of m6A-containing mRNA, such that this modification is ideally positioned to rapidly fine-tune gene
expression. We propose to take a genetic approach to determine if RNA methylation influences
oligodendrocyte lineage cell development and function. A multiprotein complex catalyzes the m6A methylation
of eukaryotic mRNA. Methyltransferase like (METTL) 3 and 14, which form a heterodimer in the m6A writer,
have been shown to be the enzymatic components of this complex, with the genetic inhibition of either
resulting in a substantial reduction of m6A-containing mRNA. Although Mettl14 null mice display embryonic
lethality, we have mice that carry a floxed allele of the Mettl14 gene that we will use in these studies. The
Mettl14 conditional mutant mice will be used in combination with a number of distinct Cre driver lines to test the
hypothesis that reversible RNA methylation plays a crucial regulatory role in oligodendrocyte development and
function. In addition, the methylated RNA transcripts expressed by oligodendrocyte lineage cells will be profiled
using an m6A-containing RNA pull-down approach in combination with RNA-sequencing. The degree to which
the m6A marks alters the stability, splicing, translation and intracellular transport of specific mRNAs in
oligodendrocytes will also be determined. Moreover, the Mettl14 gene will be inactivated in oligodendrocyte
lineage cells in adult mice to examine the requirement of methylated RNA in the maintenance of
oligodendrocyte function, as well as the response of these cells to demyelination and inflammation. These
animals will a...

## Key facts

- **NIH application ID:** 10246535
- **Project number:** 5R01NS109372-04
- **Recipient organization:** NORTHWESTERN UNIVERSITY
- **Principal Investigator:** Brian J Popko
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $349,636
- **Award type:** 5
- **Project period:** 2020-01-01 → 2023-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10246535

## Citation

> US National Institutes of Health, RePORTER application 10246535, Reversible mRNA methylation in oligodendrocyte development and CNS myelination (5R01NS109372-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10246535. Licensed CC0.

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