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
-
RNA-seq-1NCBI Gene Expression Omnibus, GSE145116.
-
RNA-seq-2NCBI Gene Expression Omnibus, GSE145117.
-
Genome-wide maps of Qki-5, Srebp2, and Pol II in oligodendrocyteNCBI Gene Expression Omnibus, GSE144756.
-
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
Version 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.
Metrics
-
- 2,010
- Page views
-
- 352
- Downloads
-
- 8
- Citations
Article citation count generated by polling the highest count across the following sources: Crossref, PubMed Central, Scopus.
Download links
A two-part list of links to download the article, or parts of the article, in various formats.
Downloads (link to download the article as PDF)
Open citations (links to open the citations from this article in various online reference manager services)
Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)
Qki regulates myelinogenesis through Srebp2-dependent cholesterol biosynthesis
eLife 10:e60467.
https://doi.org/10.7554/eLife.60467
Further reading
-
- Chromosomes and Gene Expression
- Developmental Biology
Imaging experiments reveal the complex and dynamic nature of the transcriptional hubs associated with Notch signaling.
-
- Cell Biology
- Developmental Biology
Cylicins are testis-specific proteins, which are exclusively expressed during spermiogenesis. In mice and humans, two Cylicins, the gonosomal X-linked Cylicin 1 (Cylc1/CYLC1) and the autosomal Cylicin 2 (Cylc2/CYLC2) genes, have been identified. Cylicins are cytoskeletal proteins with an overall positive charge due to lysine-rich repeats. While Cylicins have been localized in the acrosomal region of round spermatids, they resemble a major component of the calyx within the perinuclear theca at the posterior part of mature sperm nuclei. However, the role of Cylicins during spermiogenesis has not yet been investigated. Here, we applied CRISPR/Cas9-mediated gene editing in zygotes to establish Cylc1- and Cylc2-deficient mouse lines as a model to study the function of these proteins. Cylc1 deficiency resulted in male subfertility, whereas Cylc2-/-, Cylc1-/yCylc2+/-, and Cylc1-/yCylc2-/- males were infertile. Phenotypical characterization revealed that loss of Cylicins prevents proper calyx assembly during spermiogenesis. This results in decreased epididymal sperm counts, impaired shedding of excess cytoplasm, and severe structural malformations, ultimately resulting in impaired sperm motility. Furthermore, exome sequencing identified an infertile man with a hemizygous variant in CYLC1 and a heterozygous variant in CYLC2, displaying morphological abnormalities of the sperm including the absence of the acrosome. Thus, our study highlights the relevance and importance of Cylicins for spermiogenic remodeling and male fertility in human and mouse, and provides the basis for further studies on unraveling the complex molecular interactions between perinuclear theca proteins required during spermiogenesis.
