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Impact of Major Facilitator Superfamily Domain containing 2a (Mfsd2a) mediated lipid transport on oligodendrocyte lineage development at single cell level.

ABSTRACT: Mfsd2a is involved in transport of essential fatty acids such as docosahexaenoic acid (DHA) from the periphery across blood brain barrier (BBB) into the brain parenchyma. Loss of Mfsd2a in humans leads to microcephaly and hypomyelination. The significance of lipid species transported by Mfsd2a on oligodendrocyte lineage development is not known. Using OPC specific deletion of Mfsd2a (2aOKO) in mice we found that OPC cell state, differentiation and oligodendrocytes maturation is disrupted resulting in hypomyelination compared to 2afl/fl controls. Single cell RNAsequencing analysis was performed on total oligodendrocyte population from postnatal mouse brain using Ribo-TRAP mouse lines that labels complete oligodendrocyte lineage with GFP fluorescence to understand the influence of Mfsd2a on oligodendrocyte development.

ORGANISM(S): Mus musculus

PROVIDER: GSE211879 | GEO | 2023/05/17

REPOSITORIES: GEO

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Transcriptional changes in oligodendrocyte precursor cells (OPC) and immature oligodendrocytes (O4) of postnatal mouse brain due to Major Facilitator Superfamily Domain containing 2a (Mfsd2a) mediated lipid transport.

Project description:Mfsd2a plays an important role in accretion of essential fatty acids such as docosahexaenoic acid (DHA) from the periphery into the brain. Loss of Mfsd2a in humans leads to microcephaly and hypomyelination. The precise impact of lipid species transported by Mfsd2a on myelination is not known. Using OPC specific deletion of Mfsd2a (2aOKO) in mice we found that OPC cell state, differentiation and oligodendrocytes maturation is disrupted resulting in hypomyelination. RNAsequencing and differential gene expression analysis was performed on OPC and O4 cells from postnatal mouse brain to understand the influence of Mfsd2a on oligodendrocyte development.

2023-05-17 | GSE211228 | GEO

Study of vascular endothelial-specific and inducible vascular endothelial-specific deletion of Major Facilitator Superfamily Domain containing 2a (Mfsd2a) in mice.

Project description:Brain development requires a massive increase in brain lipogenesis and accretion of the essential omega-3 fatty acid docosahexaenoic acid (DHA). Brain acquisition of DHA is primarily mediated by the transporter Major Facilitator Superfamily Domain containing 2a (Mfsd2a) expressed in the endothelium of the blood-brain barrier. Mfsd2a transports DHA and other polyunsaturated fatty acids esterified to lysophosphatidylcholine (LPC-DHA). However, the function of Mfsd2a and DHA in brain development is incompletely understood. Using vascular endothelial-specific (2aECKO) and inducible vascular endothelial-specific (2aiECKO) deletion of Mfsd2a in mice, we found Mfsd2a to be uniquely required postnatally at the blood-brain barrier for normal brain growth and DHA accretion, with DHA deficiency preceding the onset of microcephaly. Gene expression profiling analysis of these DHA deficient brains indicated that Srebp-1 and Srebp-2 pathways were highly elevated. Affymetrix gene arrays were used to determine differences in gene expression between 2aECKO or 2aiECKO relative to their respective controls in the developing brain.

2018-07-11 | GSE115971 | GEO

m6A mRNA methylation is essential for oligodendrocyte maturation and CNS myelination

Project description:Oligodendrocytes are responsible for myelin formation and axonal trophic support in the vertebrate CNS. While a number of factors have been discovered that regulate oligodendrocyte lineage progression, the exact molecular mechanisms involved in this process remain unclear. Emerging studies have shown that N6-methyladenosine (m6A), the most common internal RNA modification of mammalian mRNA, plays a critical role in various developmental processes. In this study, we demonstrate that oligodendrocyte lineage progression is accompanied by changes in m6A modification on numerous transcripts. In vivo conditional inactivation in oligodendrocyte lineage cells of an essential m6A writer component, METTL14, results in decreased oligodendrocyte numbers and CNS hypomyelination, although oligodendrocyte precursor cell (OPC) numbers are normal. In vitro Mettl14 ablation disrupts post-mitotic oligodendrocyte maturation. In addition, Mettl14 ablation has distinct effects on OPC and oligodendrocyte transcriptomes. Together, our findings indicate that dynamic RNA methylation plays a critical regulatory role in oligodendrocyte development and CNS myelination.

2020-01-01 | GSE136496 | GEO

Dynamics of m6A RNA methylome during leukemogenesis reveals a role of PRMT6-MFSD2A signaling axis in maintaining AML stem cells.[RIP-seq]

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Comparison of wild-type and Mfsd2a KO eye cups

Project description:Eye photoreceptor membrane discs in outer rod segments are highly enriched in the visual pigment rhodopsin and the omega-3 fatty acid docosahexaenote (DHA). The eye acquires DHA from blood, but transporters for DHA uptake across the blood-retinal barrier (BRB) or retinal pigment epithelium have not been identified. Mfsd2a is a newly described sodium-dependent lysophosphatidylcholine symporter expressed at the BRB. Microarrays were used to determine difference in gene expression between wild-type and Mfsd2a KO eye cups. RNA was extracted from eye cups from postnatal day 13 wild-type and Mfsd2a KO mice. Equal amounts of RNA from 6 wild-type eye cups were pooled for the wild-type sample, or 6 Mfsd2a KO eye cups were pooled for the Mfsd2a KO sample. Microarray profiling was done on pooled samples with a RIN cut-off of 7.0 using Mouse 430 2.0 arrays (Affymetrix).

2016-03-23 | E-GEOD-77403 | biostudies-arrayexpress

Dynamics of m6A RNA methylome during leukemogenesis reveals a role of IGF2BP2-PRMT6-MFSD2A signaling axis in maintaining AML stem cells [MeRIP-seq]

Project description:Our data reveal that RNA m6A displays a sharp transition during leukemogenesis and involves in acquiring stem cell properties of leukemia stem cells (LSCs). We find that m6A reader IGF2BP2 and protein arginine methyltransferase PRMT6 play key roles in the acquisition of LSCs properties. Genetical deletion and pharmacological inhibition of PRMT6 delayed AML development. Mechanistically, IGF2BP2 regulates PRMT6 expression by stabilizing its mRNA in an m6A-dependent manner. PRMT6 further suppresses the expression of lipid transporter MFSD2A by establishing inactive H3R2me2a in its promoter region. Loss of PRMT6 and IGF2BP2 upregulates the expression of MFSD2A that increases the uptake of docosahexaenoic acid. Collectively, our findings uncover a critical role of IGF2BP2-PRMT6-MFSD2A signaling axis in AML development, and provide a promising therapeutic strategy for targeting LSCs.

2023-06-20 | GSE210280 | GEO

Dynamics of m6A RNA methylome during leukemogenesis reveals a role of IGF2BP2-PRMT6-MFSD2A signaling axis in maintaining AML stem cells [Prmt6 RNA-seq]

2023-06-20 | GSE210279 | GEO

Dynamics of m6A RNA methylome during leukemogenesis reveals a role of IGF2BP2-PRMT6-MFSD2A signaling axis in maintaining AML stem cells [IGF2BP2 RNA-seq]

2023-06-20 | GSE210278 | GEO

Functional characterization of DNA methylation in the oligodendrocyte lineage [RNASeq_development]

Project description:Myelination in the CNS is modulated by interplay between transcription factors and recruitment of chromatin modifying enzymes. Using a network built from genome-wide DNA methylation and transcriptomic profiling of sorted oligodendrocyte lineage cells that integrates oligodendrocyte-specific ChIP-Seq data, we defined a crucial role of DNA methylation in coordinating the transition between progenitor cell cycle arrest and oligodendrocyte differentiation. We further identified DNA methyltransferase 1 (DNMT1) as key regulator of oligodendrocyte survival at this transition point, as we detected severe and extensive developmental hypomyelination only in Olig1cre/+;Dnmt1flox/flox but not in Olig1cre/+;Dnmt3aflox/flox mice or in Cnpcre/+;Dnmt1flox/flox. This phenotype was characterized by decreased expression of genes regulating myelination and lipid metabolism â despite the hypomethylation observed at these genetic loci Â â and upregulation of cell cycle and DNA-damage pathways. Therefore DNMT1 is a nodal point regulating proliferation, survival, and differentiation in the oligodendrocyte lineage, and is critical for cell number regulation in the developing brain. mRNA profiles of FAC-sorted P2 Pdgfra::GFP and P18 Plp1-GFP purified cell samples from mouse brains were generated by RNA-sequencing, in triplicate, using Illumina HiSeq 2000.

2016-04-14 | E-GEOD-66029 | biostudies-arrayexpress

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