Abstract
The complexity of the adult brain is a result of both developmental processes and experience-dependent circuit formation. One way to look at the differences between embryonic and adult brain is to examine gene expression. Previous studies have used microarrays to address this in a global manner. However, the transcriptome is more complex than gene expression levels alone, as alternative splicing and RNA editing generate a diverse set of mature transcripts. Here we report a high-resolution transcriptome data set of mouse cerebral cortex at embryonic and adult stages using RNA sequencing (RNA-Seq). We found many differences in gene expression, splicing and RNA editing between embryonic and adult cerebral cortex. Each data set was validated technically and biologically, and in each case we found our RNA-Seq observations to have predictive validity. We provide this data set and analysis as a resource for understanding gene expression in the embryonic and adult cerebral cortex.
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Gene Expression Omnibus
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NCBI Reference Sequence
References
Innocenti, G.M. & Price, D.J. Exuberance in the development of cortical networks. Nat. Rev. Neurosci. 6, 955–965 (2005).
Price, D.J. et al. The development of cortical connections. Eur. J. Neurosci. 23, 910–920 (2006).
Mody, M. et al. Genome-wide gene expression profiles of the developing mouse hippocampus. Proc. Natl. Acad. Sci. USA 98, 8862–8867 (2001).
Kalsotra, A. & Cooper, T.A. Functional consequences of developmentally regulated alternative splicing. Nat. Rev. Genet. 12, 715–729 (2011).
Licatalosi, D.D. & Darnell, R.B. RNA processing and its regulation: global insights into biological networks. Nat. Rev. Genet. 11, 75–87 (2010).
Li, Q., Lee, J.-A. & Black, D.L. Neuronal regulation of alternative pre-mRNA splicing. Nat. Rev. Neurosci. 8, 819–831 (2007).
Wojtowicz, W.M., Flanagan, J.J., Millard, S.S., Zipursky, S.L. & Clemens, J.C. Alternative splicing of Drosophila Dscam generates axon guidance receptors that exhibit isoform-specific homophilic binding. Cell 118, 619–633 (2004).
Ullrich, B., Ushkaryov, Y.A. & Südhof, T.C. Cartography of neurexins: more than 1000 isoforms generated by alternative splicing and expressed in distinct subsets of neurons. Neuron 14, 497–507 (1995).
Hogg, M., Paro, S., Keegan, L.P. & O'Connell, M.A. RNA editing by mammalian ADARs. Adv. Genet. 73, 87–120 (2011).
Blanc, V. & Davidson, N.O. APOBEC-1-mediated RNA editing. Wiley Interdiscip. Rev. Syst. Biol. Med. 2, 594–602 (2010).
Rueter, S.M., Dawson, T.R. & Emeson, R.B. Regulation of alternative splicing by RNA editing. Nature 399, 75–80 (1999).
Serra, M.J., Smolter, P.E. & Westhof, E. Pronounced instability of tandem IU base pairs in RNA. Nucleic Acids Res. 32, 1824–1828 (2004).
Zhang, Z. & Carmichael, G.G. The fate of dsRNA in the nucleus: a p54(nrb)-containing complex mediates the nuclear retention of promiscuously A-to-I edited RNAs. Cell 106, 465–475 (2001).
Higuchi, M. et al. Point mutation in an AMPA receptor gene rescues lethality in mice deficient in the RNA-editing enzyme ADAR2. Nature 406, 78–81 (2000).
Rosenthal, J.J.C. & Seeburg, P.H. A-to-I RNA editing: effects on proteins key to neural excitability. Neuron 74, 432–439 (2012).
Wahlstedt, H., Daniel, C., Ensterö, M. & Ohman, M. Large-scale mRNA sequencing determines global regulation of RNA editing during brain development. Genome Res. 19, 978–986 (2009).
't Hoen, P.A.C. et al. Deep sequencing-based expression analysis shows major advances in robustness, resolution and inter-lab portability over five microarray platforms. Nucleic Acids Res. 36, e141 (2008).
Keane, T.M. et al. Mouse genomic variation and its effect on phenotypes and gene regulation. Nature 477, 289–294 (2011).
Anders, S. & Huber, W. Differential expression analysis for sequence count data. Genome Biol. 11, R106 (2010).
McMillan, P. et al. Tau isoform regulation is region- and cell-specific in mouse brain. J. Comp. Neurol. 511, 788–803 (2008).
Peng, Z. et al. Comprehensive analysis of RNA-Seq data reveals extensive RNA editing in a human transcriptome. Nat. Biotechnol. 30, 253–260 (2012).
Gu, T. et al. Canonical A-to-I and C-to-U RNA editing is enriched at 3′UTRs and microRNA target sites in multiple mouse tissues. PLoS ONE 7, e33720 (2012).
Nishikura, K. Functions and regulation of RNA editing by ADAR deaminases. Annu. Rev. Biochem. 79, 321–349 (2010).
Athanasiadis, A., Rich, A. & Maas, S. Widespread A-to-I RNA editing of Alu-containing mRNAs in the human transcriptome. PLoS Biol. 2, e391 (2004).
Neeman, Y., Levanon, E.Y., Jantsch, M.F. & Eisenberg, E. RNA editing level in the mouse is determined by the genomic repeat repertoire. RNA 12, 1802–1809 (2006).
DeCerbo, J. & Carmichael, G.G. SINEs point to abundant editing in the human genome. Genome Biol. 6, 216 (2005).
Semeralul, M.O. et al. Microarray analysis of the developing cortex. J. Neurobiol. 66, 1646–1658 (2006).
Kagami, Y. & Furuichi, T. Investigation of differentially expressed genes during the development of mouse cerebellum. Brain Res. Gene Expr. Patterns 1, 39–59 (2001).
Matsuki, T., Hori, G. & Furuichi, T. Gene expression profiling during the embryonic development of mouse brain using an oligonucleotide-based microarray system. Brain Res. Mol. Brain Res. 136, 231–254 (2005).
Bland, C.S. et al. Global regulation of alternative splicing during myogenic differentiation. Nucleic Acids Res. 38, 7651–7664 (2010).
Ramsköld, D., Wang, E.T., Burge, C.B. & Sandberg, R. An abundance of ubiquitously expressed genes revealed by tissue transcriptome sequence data. PLoS Comput. Biol. 5, e1000598 (2009).
McKee, A.E. et al. Exon expression profiling reveals stimulus-mediated exon use in neural cells. Genome Biol. 8, R159 (2007).
Stefl, R. & Allain, F.H.-T. A novel RNA pentaloop fold involved in targeting ADAR2. RNA 11, 592–597 (2005).
Li, M. et al. Widespread RNA and DNA sequence differences in the human transcriptome. Science 333, 53–58 (2011).
Pickrell, J.K., Gilad, Y. & Pritchard, J.K. Comment on 'Widespread RNA and DNA sequence differences in the human transcriptome'. Science 335, 1302; author reply 1302 (2012).
Kang, H.J. et al. Spatio-temporal transcriptome of the human brain. Nature 478, 483–489 (2011).
Colantuoni, C. et al. Temporal dynamics and genetic control of transcription in the human prefrontal cortex. Nature 478, 519–523 (2011).
Itoh, K. Culture of oligodendrocyte precursor cells (NG2+/O1−) and oligodendrocytes (NG2−/O1+) from embryonic rat cerebrum. Brain Res. Brain Res. Protoc. 10, 23–30 (2002).
Huang, D.W., Sherman, B.T. & Lempicki, R.A. Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources. Nat. Protoc. 4, 44–57 (2009).
Huang, D.W., Sherman, B.T. & Lempicki, R.A. Bioinformatics enrichment tools: paths toward the comprehensive functional analysis of large gene lists. Nucleic Acids Res. 37, 1–13 (2009).
Acknowledgements
The authors would like to thank E. Lindquist for excellent technical assistance. We would also like to thank M. Do for assistance with cloning experiments. This research was supported in part by the Intramural Research Program of the US National Institutes of Health, National Institute on Aging (project AG000947) and by the Swedish Research Council and Swedish Brain Power.
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A.A.D. performed the RNA-Seq experiments and analyzed the data. J.R.G. and M.A.N. provided additional analytical approaches. D.N.H., M.K.M. and I.N.R. performed mouse dissections and contributed additional validation results. M.R.C. and D.G. supervised the project. M.R.C. and A.A.D. wrote the paper with contributions from all authors.
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Supplementary information
Supplementary Text and Figures
Supplementary Figures 1–13, Supplementary Tables 1 and 5–7 (PDF 2934 kb)
Supplementary Table 2
Gene expression in the embryonic and adult mouse cerebral cortex. (CSV format) (XLS 711 kb)
Supplementary Table 3
Alternate exon usage in the embryonic and adult mouse cerebral cortex. (CSV format) (XLS 130 kb)
Supplementary Table 4
Adenosine-to-inosine RNA editing in the embryonic and adult mouse cerebral cortex. (CSV format) (XLS 44 kb)
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Dillman, A., Hauser, D., Gibbs, J. et al. mRNA expression, splicing and editing in the embryonic and adult mouse cerebral cortex. Nat Neurosci 16, 499–506 (2013). https://doi.org/10.1038/nn.3332
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DOI: https://doi.org/10.1038/nn.3332
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