Qki regulates myelinogenesis through Srebp2-dependent cholesterol biosynthesis
- MD Anderson Cancer Center, United States
- Fudan University, China
- Baylor College of Medicine, United States
- Chinese Academy of Medical Sciences and Peking Union Medical College, China
- Tufts University, United States
Abstract
Myelination depends on timely, precise control of oligodendrocyte differentiation and myelinogenesis. Cholesterol is the most abundant component of myelin and essential for myelin membrane assembly in the central nervous system. However, the underlying mechanisms of precise control of cholesterol biosynthesis in oligodendrocytes remain elusive. In the present study, we found that Qki depletion in neural stem cells or oligodendrocyte precursor cells in neonatal mice resulted in impaired cholesterol biosynthesis and defective myelinogenesis without compromising their differentiation into Aspa+Gstpi+ myelinating oligodendrocytes. Mechanistically, Qki-5 functions as a co-activator of Srebp2 to control transcription of the genes involved in cholesterol biosynthesis in oligodendrocytes. Consequently, Qki depletion led to substantially reduced concentration of the cholesterol in mouse brain, impairing proper myelin assembly. Our study demonstrated that Qki-Srebp2–controlled cholesterol biosynthesis is indispensable for myelinogenesis and highlights a novel function of Qki as a transcriptional co-activator beyond its canonical function as an RNA-binding protein.
Data availability
Sequencing data have been deposited in GEO under accession codes GSE145116, GSE145117 and GSE144756
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RNA-seq-1NCBI Gene Expression Omnibus, GSE145116.
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RNA-seq-2NCBI Gene Expression Omnibus, GSE145117.
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Genome-wide maps of Qki-5, Srebp2, and Pol II in oligodendrocyteNCBI Gene Expression Omnibus, GSE144756.
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Genome-wide maps of Qki-5 and PPARb in mouse oligodendrocytesNCBI Gene Expression Omnibus, GSE126577.
Article and author information
Author details
Funding
NCI (R37CA214800)
- Jian Hu
MD Anderson Cancer Center (startup)
- Jian Hu
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: All mouse experiments were conducted in accordance with protocols approved by the MD Anderson Institutional Animal Care and Use Committee. (IACUC Study #00001392-RN01)
Reviewing Editor
- Jian Xu, University of Texas Southwestern Medical Center, United States
Publication history
- Received: June 26, 2020
- Accepted: May 1, 2021
- Accepted Manuscript published: May 4, 2021 (version 1)
- Version of Record published: May 21, 2021 (version 2)
Copyright
© 2021, Zhou et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Qki regulates myelinogenesis through Srebp2-dependent cholesterol biosynthesis
eLife 10:e60467.
https://doi.org/10.7554/eLife.60467
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