Loss of Quaking RNA binding protein disrupts the expression of genes associated with astrocyte maturation in mouse brain.
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
09 03 2021
09 03 2021
Historique:
received:
26
10
2020
accepted:
09
02
2021
entrez:
22
3
2021
pubmed:
23
3
2021
medline:
7
4
2021
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 33750804
doi: 10.1038/s41467-021-21703-5
pii: 10.1038/s41467-021-21703-5
pmc: PMC7943582
doi:
Substances chimiques
Mbp protein, mouse
0
Myelin Basic Protein
0
Protein Isoforms
0
Qk protein, mouse
0
RNA, Messenger
0
RNA-Binding Proteins
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
1537Subventions
Organisme : NIMH NIH HHS
ID : R01 MH116999
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA091842
Pays : United States
Organisme : NICHD NIH HHS
ID : P50 HD103525
Pays : United States
Organisme : NCATS NIH HHS
ID : UL1 TR002345
Pays : United States
Organisme : NINDS NIH HHS
ID : R01 NS102272
Pays : United States
Références
Andreassi, C. & Riccio, A. To localize or not to localize: mRNA fate is in 3′UTR ends. Trends Cell Biol. 19, 465–474 (2009).
pubmed: 19716303
doi: 10.1016/j.tcb.2009.06.001
Huang, Y.-S., Carson, J. H., Barbarese, E. & Richter, J. D. Facilitation of dendritic mRNA transport by CPEB. Genes Dev. 17, 638–653 (2003).
pubmed: 12629046
pmcid: 196011
doi: 10.1101/gad.1053003
Darnell, J. C. et al. FMRP stalls ribosomal translocation on mRNAs linked to synaptic function and autism. Cell 146, 247–261 (2011).
pubmed: 21784246
pmcid: 3232425
doi: 10.1016/j.cell.2011.06.013
Wang, E. T. et al. Dysregulation of mRNA localization and translation in genetic disease. J. Neurosci. J. Soc. Neurosci. 36, 11418–11426 (2016).
doi: 10.1523/JNEUROSCI.2352-16.2016
Sakers, K. et al. Astrocytes locally translate transcripts in their peripheral processes. Proc. Natl Acad. Sci. USA. 114, E3830–E3838 (2017).
pubmed: 28439016
doi: 10.1073/pnas.1617782114
pmcid: 5441704
Lee, J.-A. et al. Cytoplasmic Rbfox1 regulates the expression of synaptic and autism-related genes. Neuron 89, 113–128 (2016).
pubmed: 26687839
doi: 10.1016/j.neuron.2015.11.025
Boutej, H. et al. Diverging mRNA and protein networks in activated microglia reveal SRSF3 suppresses translation of highly upregulated innate immune transcripts. Cell Rep. 21, 3220–3233 (2017).
pubmed: 29241548
doi: 10.1016/j.celrep.2017.11.058
Li, Z., Zhang, Y., Li, D. & Feng, Y. Destabilization and mislocalization of myelin basic protein mRNAs in quaking dysmyelination lacking the QKI RNA-binding proteins. J. Neurosci. J. Soc. Neurosci. 20, 4944–4953 (2000).
doi: 10.1523/JNEUROSCI.20-13-04944.2000
Higashimori, H. et al. Selective deletion of astroglial FMRP dysregulates glutamate transporter GLT1 and contributes to fragile X syndrome phenotypes in vivo. J. Neurosci. J. Soc. Neurosci. 36, 7079–7094 (2016).
doi: 10.1523/JNEUROSCI.1069-16.2016
Pilaz, L.-J., Lennox, A. L., Rouanet, J. P. & Silver, D. L. Dynamic mRNA transport and local translation in radial glial progenitors of the developing brain. Curr. Biol. CB 26, 3383–3392 (2016).
pubmed: 27916527
doi: 10.1016/j.cub.2016.10.040
Chen, T. & Richard, S. Structure-function analysis of Qk1: a lethal point mutation in mouse quaking prevents homodimerization. Mol. Cell. Biol. 18, 4863–4871 (1998).
pubmed: 9671495
pmcid: 109071
doi: 10.1128/MCB.18.8.4863
Li, Z. et al. Defective smooth muscle development in qkI-deficient mice. Dev. Growth Differ. 45, 449–462 (2003).
pubmed: 14706070
doi: 10.1111/j.1440-169X.2003.00712.x
Jan, E., Motzny, C. K., Graves, L. E. & Goodwin, E. B. The STAR protein, GLD-1, is a translational regulator of sexual identity in Caenorhabditis elegans. EMBO J. 18, 258–269 (1999).
pubmed: 9878068
pmcid: 1171120
doi: 10.1093/emboj/18.1.258
Boisvert, M. M., Erikson, G. A., Shokhirev, M. N. & Allen, N. J. The aging astrocyte transcriptome from multiple regions of the mouse brain. Cell Rep. 22, 269–285 (2018).
pubmed: 29298427
pmcid: 5783200
doi: 10.1016/j.celrep.2017.12.039
Clarke, L. E. et al. Normal aging induces A1-like astrocyte reactivity. Proc. Natl Acad. Sci. USA. 115, E1896–E1905 (2018).
pubmed: 29437957
doi: 10.1073/pnas.1800165115
pmcid: 5828643
Hardy, R. J. et al. Neural cell type-specific expression of QKI proteins is altered in quakingviable mutant mice. J. Neurosci. J. Soc. Neurosci. 16, 7941–7949 (1996).
doi: 10.1523/JNEUROSCI.16-24-07941.1996
Larocque, D. et al. Protection of p27(Kip1) mRNA by quaking RNA binding proteins promotes oligodendrocyte differentiation. Nat. Neurosci. 8, 27–33 (2005).
pubmed: 15568022
doi: 10.1038/nn1359
Zhao, L. et al. QKI binds MAP1B mRNA and enhances MAP1B expression during oligodendrocyte development. Mol. Biol. Cell 17, 4179–4186 (2006).
pubmed: 16855020
pmcid: 1635361
doi: 10.1091/mbc.e06-04-0355
Doukhanine, E., Gavino, C., Haines, J. D., Almazan, G. & Richard, S. The QKI-6 RNA binding protein regulates actin-interacting protein-1 mRNA stability during oligodendrocyte differentiation. Mol. Biol. Cell 21, 3029–3040 (2010).
pubmed: 20631256
pmcid: 2929996
doi: 10.1091/mbc.e10-04-0305
Larocque, D. et al. Nuclear retention of MBP mRNAs in the quaking viable mice. Neuron 36, 815–829 (2002).
pubmed: 12467586
doi: 10.1016/S0896-6273(02)01055-3
Zhang, Y. et al. An RNA-sequencing transcriptome and splicing database of glia, neurons, and vascular cells of the cerebral cortex. J. Neurosci. 34, 11929–11947 (2014).
pubmed: 25186741
pmcid: 4152602
doi: 10.1523/JNEUROSCI.1860-14.2014
Zhang, Y. et al. Purification and characterization of progenitor and mature human astrocytes reveals transcriptional and functional differences with mouse. Neuron 89, 37–53 (2016).
pubmed: 26687838
doi: 10.1016/j.neuron.2015.11.013
Jiang, L., Saetre, P., Radomska, K. J., Jazin, E. & Lindholm Carlström, E. QKI-7 regulates expression of interferon-related genes in human astrocyte glioma cells. PloS One 5, e13079 (2010).
Wu, J. I., Reed, R. B., Grabowski, P. J. & Artzt, K. Function of quaking in myelination: regulation of alternative splicing. Proc. Natl Acad. Sci. USA. 99, 4233–4238 (2002).
pubmed: 11917126
doi: 10.1073/pnas.072090399
pmcid: 123631
Radomska, K. J. et al. RNA-binding protein QKI regulates Glial fibrillary acidic protein expression in human astrocytes. Hum. Mol. Genet. 22, 1373–1382 (2013).
pubmed: 23321059
doi: 10.1093/hmg/dds553
Farnsworth, B. et al. QKI6B mRNA levels are upregulated in schizophrenia and predict GFAP expression. Brain Res. 1669, 63–68 (2017).
pubmed: 28552414
doi: 10.1016/j.brainres.2017.05.027
Ebersole, T. A., Chen, Q., Justice, M. J. & Artzt, K. The quaking gene product necessary in embryogenesis and myelination combines features of RNA binding and signal transduction proteins. Nat. Genet. 12, 260–265 (1996).
pubmed: 8589716
doi: 10.1038/ng0396-260
Hayakawa-Yano, Y. et al. An RNA-binding protein, Qki5, regulates embryonic neural stem cells through pre-mRNA processing in cell adhesion signaling. Genes Dev. 31, 1910–1925 (2017).
pubmed: 29021239
pmcid: 5693031
doi: 10.1101/gad.300822.117
Sakers, K. et al. Astrocytes locally translate transcripts in their peripheral processes. Proc. Natl Acad. Sci. USA. 114, E3830–E3838 (2017).
pubmed: 28439016
doi: 10.1073/pnas.1617782114
pmcid: 5441704
Bailey, T. L., Johnson, J., Grant, C. E. & Noble, W. S. The MEME suite. Nucleic Acids Res. 43, W39–W49 (2015).
pubmed: 25953851
pmcid: 4489269
doi: 10.1093/nar/gkv416
Galarneau, A. & Richard, S. Target RNA motif and target mRNAs of the Quaking STAR protein. Nat. Struct. Mol. Biol. 12, 691–698 (2005).
pubmed: 16041388
doi: 10.1038/nsmb963
Fagg, W. S. et al. Autogenous cross-regulation of Quaking mRNA processing and translation balances Quaking functions in splicing and translation. Genes Dev. 31, 1894–1909 (2017).
pubmed: 29021242
pmcid: 5695090
doi: 10.1101/gad.302059.117
Tushev, G. et al. Alternative 3′ UTRs modify the localization, regulatory potential, stability, and plasticity of mRNAs in neuronal compartments. Neuron (2018) https://doi.org/10.1016/j.neuron.2018.03.030 .
Theil, K., Herzog, M. & Rajewsky, N. Post-transcriptional regulation by 3′ UTRs can be masked by regulatory elements in 5′ UTRs. Cell Rep. 22, 3217–3226 (2018).
pubmed: 29562178
doi: 10.1016/j.celrep.2018.02.094
Teplova, M. et al. Structure–function studies of STAR family Quaking proteins bound to their in vivo RNA target sites. Genes Dev. 27, 928–940 (2013).
pubmed: 23630077
pmcid: 3650229
doi: 10.1101/gad.216531.113
Xu, X., Wells, A. B., O’Brien, D. R., Nehorai, A. & Dougherty, J. D. Cell type-specific expression analysis to identify putative cellular mechanisms for neurogenetic disorders. J. Neurosci. J. Soc. Neurosci. 34, 1420–1431 (2014).
doi: 10.1523/JNEUROSCI.4488-13.2014
Wu, H. Y., Dawson, M. R. L., Reynolds, R. & Hardy, R. J. Expression of QKI proteins and MAP1B identifies actively myelinating oligodendrocytes in adult rat brain. Mol. Cell. Neurosci. 17, 292–302 (2001).
pubmed: 11178867
doi: 10.1006/mcne.2000.0941
Dougherty, J. D. et al. PBK/TOPK, a proliferating neural progenitor-specific mitogen-activated protein kinase kinase. J. Neurosci. 25, 10773–10785 (2005).
pubmed: 16291951
pmcid: 6725850
doi: 10.1523/JNEUROSCI.3207-05.2005
Menn, B. et al. Origin of oligodendrocytes in the subventricular zone of the adult brain. J. Neurosci. 26, 7907–7918 (2006).
pubmed: 16870736
pmcid: 6674207
doi: 10.1523/JNEUROSCI.1299-06.2006
Casper, K. B. & McCarthy, K. D. GFAP-positive progenitor cells produce neurons and oligodendrocytes throughout the CNS. Mol. Cell. Neurosci. 31, 676–684 (2006).
pubmed: 16458536
doi: 10.1016/j.mcn.2005.12.006
Suzuki, N. et al. Differentiation of oligodendrocyte precursor cells from Sox10 -venus mice to oligodendrocytes and astrocytes. Sci. Rep. 7, 1–11 (2017).
doi: 10.1038/s41598-017-14207-0
Yang, Y., Higashimori, H. & Morel, L. Developmental maturation of astrocytes and pathogenesis of neurodevelopmental disorders. J. Neurodev. Disord. 5, 22 (2013).
pubmed: 23988237
pmcid: 3765765
doi: 10.1186/1866-1955-5-22
Stogsdill, J. A. et al. Astrocytic neuroligins control astrocyte morphogenesis and synaptogenesis. Nature 551, 192–197 (2017).
pubmed: 29120426
pmcid: 5796651
doi: 10.1038/nature24638
Saccomanno, L. et al. The STAR protein QKI-6 is a translational repressor. Proc. Natl Acad. Sci. USA. 96, 12605–12610 (1999).
pubmed: 10535969
doi: 10.1073/pnas.96.22.12605
pmcid: 23011
Zearfoss, N. R., Clingman, C. C., Farley, B. M., McCoig, L. M. & Ryder, S. P. Quaking regulates Hnrnpa1 expression through Its 3′ UTR in oligodendrocyte precursor cells. PLOS Genet 7, e1001269 (2011).
pubmed: 21253564
pmcid: 3017110
doi: 10.1371/journal.pgen.1001269
Conn, S. J. et al. The RNA binding protein quaking regulates formation of circRNAs. Cell 160, 1125–1134 (2015).
pubmed: 25768908
doi: 10.1016/j.cell.2015.02.014
Justice, M. J. & Bode, V. C. Three ENU-induced alleles of the murine quaking locus are recessive embryonic lethal mutations. Genet. Res. 51, 95–102 (1988).
pubmed: 3410318
doi: 10.1017/S0016672300024101
Foo, L. C. & Dougherty, J. D. Aldh1L1 is expressed by postnatal neural stem cells in vivo. Glia 61, 1533–1541 (2013).
pubmed: 23836537
pmcid: 3777382
doi: 10.1002/glia.22539
Srinivasan, R. et al. New transgenic mouse lines for selectively targeting astrocytes and studying calcium signals in astrocyte processes in situ and in vivo. Neuron 92, 1181–1195 (2016).
pubmed: 27939582
pmcid: 5403514
doi: 10.1016/j.neuron.2016.11.030
Takeuchi, A. et al. Identification of Qk as a glial precursor cell marker that governs the fate specification of neural stem cells to a glial cell lineage. Stem Cell Rep. 15, 883–897 (2020).
doi: 10.1016/j.stemcr.2020.08.010
Cachón-González, M. B., Zaccariotto, E. & Cox, T. M. Genetics and therapies for GM2 gangliosidosis. Curr. Gene Ther. 18, 68–89 (2018).
pubmed: 29618308
pmcid: 6040173
doi: 10.2174/1566523218666180404162622
Ren, J. et al. Qki is an essential regulator of microglial phagocytosis in demyelination. J. Exp. Med. 218, e20190348 (2021).
pubmed: 33045062
doi: 10.1084/jem.20190348
Uren, P. J. et al. Site identification in high-throughput RNA-protein interaction data. Bioinforma. Oxf. Engl. 28, 3013–3020 (2012).
doi: 10.1093/bioinformatics/bts569
Liao, Y., Smyth, G. K. & Shi, W. The Subread aligner: fast, accurate and scalable read mapping by seed-and-vote. Nucleic Acids Res. 41, e108 (2013).
pubmed: 23558742
pmcid: 3664803
doi: 10.1093/nar/gkt214
Dougherty, J. D., Schmidt, E. F., Nakajima, M. & Heintz, N. Analytical approaches to RNA profiling data for the identification of genes enriched in specific cells. Nucleic Acids Res. 38, 4218–4230 (2010).
pubmed: 20308160
pmcid: 2910036
doi: 10.1093/nar/gkq130
Dougherty, J. D. et al. Candidate pathways for promoting differentiation or quiescence of oligodendrocyte progenitor-like cells in glioma. Cancer Res. 72, 4856–4868 (2012).
pubmed: 22865458
pmcid: 3543775
doi: 10.1158/0008-5472.CAN-11-2632