Loss of Quaking RNA binding protein disrupts the expression of genes associated with astrocyte maturation in mouse brain

Kristina Sakers, Yating Liu, Lorida Llaci, Scott M. Lee, Michael J. Vasek, Michael A. Rieger, Sean Brophy, Eric Tycksen, Renate Lewis, Susan E. Maloney and Joseph D. Dougherty ()
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Kristina Sakers: Washington University School of Medicine
Yating Liu: Washington University School of Medicine
Lorida Llaci: Washington University School of Medicine
Scott M. Lee: Washington University School of Medicine
Michael J. Vasek: Washington University School of Medicine
Michael A. Rieger: Washington University School of Medicine
Sean Brophy: Washington University School of Medicine
Eric Tycksen: Washington University School of Medicine
Renate Lewis: Hope Center, Washington University School of Medicine and Saint Louis University
Susan E. Maloney: Washington University School of Medicine
Joseph D. Dougherty: Washington University School of Medicine

Nature Communications, 2021, vol. 12, issue 1, 1-14

Abstract: Abstract Quaking RNA binding protein (QKI) is essential for oligodendrocyte development as myelination requires myelin basic protein mRNA regulation and localization by the cytoplasmic isoforms (e.g., QKI-6). QKI-6 is also highly expressed in astrocytes, which were recently demonstrated to have regulated mRNA localization. Here, we define the targets of QKI in the mouse brain via CLIPseq and we show that QKI-6 binds 3′UTRs of a subset of astrocytic mRNAs. Binding is also enriched near stop codons, mediated partially by QKI-binding motifs (QBMs), yet spreads to adjacent sequences. Using a viral approach for mosaic, astrocyte-specific gene mutation with simultaneous translating RNA sequencing (CRISPR-TRAPseq), we profile ribosome associated mRNA from QKI-null astrocytes in the mouse brain. This demonstrates a role for QKI in stabilizing CLIP-defined direct targets in astrocytes in vivo and further shows that QKI mutation disrupts the transcriptional changes for a discrete subset of genes associated with astrocyte maturation.

Date: 2021
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DOI: 10.1038/s41467-021-21703-5

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