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PMID: 25525873 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

A highly conserved program of neuronal microexons is misregulated in autistic brains.

Cell ·Vol. 159 ·No. 7 ·2014-12-18 ·Pages 1511-23

Irimia M, Weatheritt RJ, Ellis JD, Parikshak NN, Gonatopoulos-Pournatzis T, Babor M, Quesnel-Vallières M, Tapial J, Raj B, O'Hanlon D, Barrios-Rodiles M, Sternberg MJ, Cordes SP, Roth FP, Wrana JL, Geschwind DH, Blencowe BJ

Abstract

Alternative splicing (AS) generates vast transcriptomic and proteomic complexity. However, which of the myriad of detected AS events provide important biological functions is not well understood. Here, we define the largest program of functionally coordinated, neural-regulated AS described to date in mammals. Relative to all other types of AS within this program, 3-15 nucleotide "microexons" display the most striking evolutionary conservation and switch-like regulation. These microexons modulate the function of interaction domains of proteins involved in neurogenesis. Most neural microexons are regulated by the neuronal-specific splicing factor nSR100/SRRM4, through its binding to adjacent intronic enhancer motifs. Neural microexons are frequently misregulated in the brains of individuals with autism spectrum disorder, and this misregulation is associated with reduced levels of nSR100. The results thus reveal a highly conserved program of dynamic microexon regulation associated with the remodeling of protein-interaction networks during neurogenesis, the misregulation of which is linked to autism.

MeSH Terms
Alternative Splicing Animals Child Development Disorders, Pervasive/metabolism,pathology Humans Mice Models, Molecular Nerve Tissue Proteins/chemistry,genetics,metabolism Neurogenesis Neurons/metabolism Protein Interaction Domains and Motifs Sequence Analysis, RNA Temporal Lobe/pathology
Chemicals
Nerve Tissue Proteins SRRM4 protein, human
Authors & Affiliations
17 authors, click to expand affiliations / ORCID
Irimia Manuel
Donnelly Centre, University of Toronto, 160 College Street, Toronto, ON M5S 3E1, Canada; EMBL/CRG Research Unit in Systems Biology, Centre for Genomic Regulation (CRG), 88 Dr. Aiguader, Barcelona 08003, Spain. Electronic address: [email protected].
Weatheritt Robert J
Donnelly Centre, University of Toronto, 160 College Street, Toronto, ON M5S 3E1, Canada; MRC Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge CB2 0QH, UK.
Ellis Jonathan D
Donnelly Centre, University of Toronto, 160 College Street, Toronto, ON M5S 3E1, Canada.
Parikshak Neelroop N
Department of Neurology, Center for Autism Research and Treatment, Semel Institute, David Geffen School of Medicine, University of California Los Angeles, 695 Charles E. Young Drive South, Los Angeles, CA 90095, USA.
Gonatopoulos-Pournatzis Thomas
Donnelly Centre, University of Toronto, 160 College Street, Toronto, ON M5S 3E1, Canada.
Babor Mariana
Donnelly Centre, University of Toronto, 160 College Street, Toronto, ON M5S 3E1, Canada.
Quesnel-Vallières Mathieu
Donnelly Centre, University of Toronto, 160 College Street, Toronto, ON M5S 3E1, Canada.
Tapial Javier
EMBL/CRG Research Unit in Systems Biology, Centre for Genomic Regulation (CRG), 88 Dr. Aiguader, Barcelona 08003, Spain.
Raj Bushra
Donnelly Centre, University of Toronto, 160 College Street, Toronto, ON M5S 3E1, Canada.
O'Hanlon Dave
Donnelly Centre, University of Toronto, 160 College Street, Toronto, ON M5S 3E1, Canada.
Barrios-Rodiles Miriam
Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, 600 University Avenue, Toronto, ON M5G 1X5, Canada.
Sternberg Michael J E
Centre for Integrative Systems Biology and Bioinformatics, Department of Life Sciences, Imperial College London, London SW7 2AZ, UK.
Cordes Sabine P
Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, 600 University Avenue, Toronto, ON M5G 1X5, Canada; Department of Molecular Genetics, University of Toronto, 1 King's College Circle, Toronto, ON M5S 1A8, Canada.
Roth Frederick P
Donnelly Centre, University of Toronto, 160 College Street, Toronto, ON M5S 3E1, Canada; Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, 600 University Avenue, Toronto, ON M5G 1X5, Canada; Department of Molecular Genetics, University of Toronto, 1 King's College Circle, Toronto, ON M5S 1A8, Canada; Department of Computer Science, University of Toronto, 10 King's College Road, Toronto, ON M5S 3G4, Canada; Canadian Institute For Advanced Research, 180 Dundas Street West, Toronto, ON M5G 1Z8, Canada.
Wrana Jeffrey L
Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, 600 University Avenue, Toronto, ON M5G 1X5, Canada; Department of Molecular Genetics, University of Toronto, 1 King's College Circle, Toronto, ON M5S 1A8, Canada.
Geschwind Daniel H
Department of Neurology, Center for Autism Research and Treatment, Semel Institute, David Geffen School of Medicine, University of California Los Angeles, 695 Charles E. Young Drive South, Los Angeles, CA 90095, USA.
Blencowe Benjamin J
Donnelly Centre, University of Toronto, 160 College Street, Toronto, ON M5S 3E1, Canada; Department of Molecular Genetics, University of Toronto, 1 King's College Circle, Toronto, ON M5S 1A8, Canada. Electronic address: [email protected].
References (63)
63 references, click to expand
  1. NOVA-dependent regulation of cryptic NMD exons controls synaptic protein levels after seizure.
    Elife. 2013;2:e00178 PMID: 23359859
  2. Linear motifs confer functional diversity onto splice variants.
    Nucleic Acids Res. 2012 Aug;40(15):7123-31 PMID: 22638587
  3. OLego: fast and sensitive mapping of spliced mRNA-Seq reads using small seeds.
    Nucleic Acids Res. 2013 May 1;41(10):5149-63 PMID: 23571760
  4. Functional consequences of developmentally regulated alternative splicing.
    Nat Rev Genet. 2011 Oct;12(10):715-29 PMID: 21921927
  5. Alternative splicing in concert with protein intrinsic disorder enables increased functional diversity in multicellular organisms.
    Proc Natl Acad Sci U S A. 2006 May 30;103(22):8390-5 PMID: 16717195
  6. Computational discovery of internal micro-exons.
    Genome Res. 2003 Jun;13(6A):1216-21 PMID: 12799353
  7. Nova regulates brain-specific splicing to shape the synapse.
    Nat Genet. 2005 Aug;37(8):844-52 PMID: 16041372
  8. Tip60 HAT activity mediates APP induced lethality and apoptotic cell death in the CNS of a Drosophila Alzheimer's disease model.
    PLoS One. 2012;7(7):e41776 PMID: 22848598
  9. Fe65 is required for Tip60-directed histone H4 acetylation at DNA strand breaks.
    Proc Natl Acad Sci U S A. 2009 Mar 31;106(13):5093-8 PMID: 19282473
  10. The amyloid precursor protein and its regulatory protein, FE65, in growth cones and synapses in vitro and in vivo.
    J Neurosci. 2003 Jul 2;23(13):5407-15 PMID: 12843239
  11. 5-hmC in the brain is abundant in synaptic genes and shows differences at the exon-intron boundary.
    Nat Struct Mol Biol. 2012 Oct;19(10):1037-43 PMID: 22961382
  12. Functional coordination of alternative splicing in the mammalian central nervous system.
    Genome Biol. 2007;8(6):R108 PMID: 17565696
  13. Identification and characterization of a neuron-specific isoform of protrudin.
    Genes Cells. 2014 Feb;19(2):97-111 PMID: 24251978
  14. The spliceosome: design principles of a dynamic RNP machine.
    Cell. 2009 Feb 20;136(4):701-18 PMID: 19239890
  15. Clinical, cellular, and neuropathological consequences of AP1S2 mutations: further delineation of a recognizable X-linked mental retardation syndrome.
    Hum Mutat. 2008 Jul;29(7):966-74 PMID: 18428203
  16. Networking in a global world: establishing functional connections between neural splicing regulators and their target transcripts.
    RNA. 2011 May;17(5):775-91 PMID: 21415141
  17. A noise-reduction GWAS analysis implicates altered regulation of neurite outgrowth and guidance in autism.
    Mol Autism. 2011 Jan 19;2(1):1 PMID: 21247446
  18. A global regulatory mechanism for activating an exon network required for neurogenesis.
    Mol Cell. 2014 Oct 2;56(1):90-103 PMID: 25219497
  19. Does steric interference between splice sites block the splicing of a short c-src neuron-specific exon in non-neuronal cells?
    Genes Dev. 1991 Mar;5(3):389-402 PMID: 2001841
  20. Integrative functional genomic analyses implicate specific molecular pathways and circuits in autism.
    Cell. 2013 Nov 21;155(5):1008-21 PMID: 24267887
  21. High-throughput mapping of a dynamic signaling network in mammalian cells.
    Science. 2005 Mar 11;307(5715):1621-5 PMID: 15761153
  22. Transcript assembly and quantification by RNA-Seq reveals unannotated transcripts and isoform switching during cell differentiation.
    Nat Biotechnol. 2010 May;28(5):511-5 PMID: 20436464
  23. Transcriptomic analysis of autistic brain reveals convergent molecular pathology.
    Nature. 2011 Jun 16;474(7351):380-4 PMID: 21614001
  24. Microexon-based regulation of ITSN1 and Src SH3 domains specificity relies on introduction of charged amino acids into the interaction interface.
    Biochem Biophys Res Commun. 2010 Aug 20;399(2):307-12 PMID: 20659428
  25. RNA processing and its regulation: global insights into biological networks.
    Nat Rev Genet. 2010 Jan;11(1):75-87 PMID: 20019688
  26. A transcriptionally [correction of transcriptively] active complex of APP with Fe65 and histone acetyltransferase Tip60.
    Science. 2001 Jul 6;293(5527):115-20 PMID: 11441186
  27. Tissue-specific splicing of disordered segments that embed binding motifs rewires protein interaction networks.
    Mol Cell. 2012 Jun 29;46(6):871-83 PMID: 22749400
  28. A census of human soluble protein complexes.
    Cell. 2012 Aug 31;150(5):1068-81 PMID: 22939629
  29. The APP-interacting protein FE65 is required for hippocampus-dependent learning and long-term potentiation.
    Learn Mem. 2009 Sep;16(9):537-44 PMID: 19713352
  30. An RNA-sequencing transcriptome and splicing database of glia, neurons, and vascular cells of the cerebral cortex.
    J Neurosci. 2014 Sep 3;34(36):11929-47 PMID: 25186741
  31. Clathrin.
    Annu Rev Biochem. 2000;69:699-727 PMID: 10966473
  32. Dysregulation of synaptogenesis genes antecedes motor neuron pathology in spinal muscular atrophy.
    Proc Natl Acad Sci U S A. 2013 Nov 26;110(48):19348-53 PMID: 24191055
  33. Widespread intron retention in mammals functionally tunes transcriptomes.
    Genome Res. 2014 Nov;24(11):1774-86 PMID: 25258385
  34. The evolutionary landscape of alternative splicing in vertebrate species.
    Science. 2012 Dec 21;338(6114):1587-93 PMID: 23258890
  35. GMAP: a genomic mapping and alignment program for mRNA and EST sequences.
    Bioinformatics. 2005 May 1;21(9):1859-75 PMID: 15728110
  36. Alternative pre-mRNA splicing regulation in cancer: pathways and programs unhinged.
    Genes Dev. 2010 Nov 1;24(21):2343-64 PMID: 21041405
  37. Isoform-specific knockout of FE65 leads to impaired learning and memory.
    J Neurosci Res. 2004 Jan 1;75(1):12-24 PMID: 14689444
  38. Listening to silence and understanding nonsense: exonic mutations that affect splicing.
    Nat Rev Genet. 2002 Apr;3(4):285-98 PMID: 11967553
  39. The invected gene of Drosophila: sequence analysis and expression studies reveal a close kinship to the engrailed gene.
    Genes Dev. 1987 Mar;1(1):19-28 PMID: 2892756
  40. FE65 interacts with ADP-ribosylation factor 6 to promote neurite outgrowth.
    FASEB J. 2014 Jan;28(1):337-49 PMID: 24056087
  41. Epigenetic dysregulation of SHANK3 in brain tissues from individuals with autism spectrum disorders.
    Hum Mol Genet. 2014 Mar 15;23(6):1563-78 PMID: 24186872
  42. Cohesin-mediated interactions organize chromosomal domain architecture.
    EMBO J. 2013 Dec 11;32(24):3119-29 PMID: 24185899
  43. Alternative isoform regulation in human tissue transcriptomes.
    Nature. 2008 Nov 27;456(7221):470-6 PMID: 18978772
  44. Revealing global regulatory features of mammalian alternative splicing using a quantitative microarray platform.
    Mol Cell. 2004 Dec 22;16(6):929-41 PMID: 15610736
  45. Mechanisms of alternative splicing regulation: insights from molecular and genomics approaches.
    Nat Rev Mol Cell Biol. 2009 Nov;10(11):741-54 PMID: 19773805
  46. Dynamic integration of splicing within gene regulatory pathways.
    Cell. 2013 Mar 14;152(6):1252-69 PMID: 23498935
  47. Mutations in the gene encoding the Sigma 2 subunit of the adaptor protein 1 complex, AP1S2, cause X-linked mental retardation.
    Am J Hum Genet. 2006 Dec;79(6):1119-24 PMID: 17186471
  48. LSD1 Neurospecific Alternative Splicing Controls Neuronal Excitability in Mouse Models of Epilepsy.
    Cereb Cortex. 2015 Sep;25(9):2729-40 PMID: 24735673
  49. Rare de novo variants associated with autism implicate a large functional network of genes involved in formation and function of synapses.
    Neuron. 2011 Jun 9;70(5):898-907 PMID: 21658583
  50. Alternative splicing: decoding an expansive regulatory layer.
    Curr Opin Cell Biol. 2012 Jun;24(3):323-32 PMID: 22465326
  51. A post-transcriptional regulatory switch in polypyrimidine tract-binding proteins reprograms alternative splicing in developing neurons.
    Genes Dev. 2007 Jul 1;21(13):1636-52 PMID: 17606642
  52. Evolutionary dynamics of gene and isoform regulation in Mammalian tissues.
    Science. 2012 Dec 21;338(6114):1593-9 PMID: 23258891
  53. Regulation of vertebrate nervous system alternative splicing and development by an SR-related protein.
    Cell. 2009 Sep 4;138(5):898-910 PMID: 19737518
  54. Protein interaction network of alternatively spliced isoforms from brain links genetic risk factors for autism.
    Nat Commun. 2014;5:3650 PMID: 24722188
  55. Segmental distribution of bithorax complex proteins during Drosophila development.
    Nature. 1985 Feb 14-20;313(6003):545-51 PMID: 3918274
  56. Deep surveying of alternative splicing complexity in the human transcriptome by high-throughput sequencing.
    Nat Genet. 2008 Dec;40(12):1413-5 PMID: 18978789
  57. Tissue-specific alternative splicing remodels protein-protein interaction networks.
    Mol Cell. 2012 Jun 29;46(6):884-92 PMID: 22749401
  58. Signal-mediated, AP-1/clathrin-dependent sorting of transmembrane receptors to the somatodendritic domain of hippocampal neurons.
    Neuron. 2012 Sep 6;75(5):810-23 PMID: 22958822
  59. Misregulated RNA processing in amyotrophic lateral sclerosis.
    Brain Res. 2012 Jun 26;1462:3-15 PMID: 22444279
  60. MBNL proteins repress ES-cell-specific alternative splicing and reprogramming.
    Nature. 2013 Jun 13;498(7453):241-5 PMID: 23739326
  61. A macromolecular complex involving the amyloid precursor protein (APP) and the cytosolic adapter FE65 is a negative regulator of axon branching.
    Mol Cell Neurosci. 2007 May;35(1):57-63 PMID: 17383198
  62. Longitudinal RNA sequencing of the deep transcriptome during neurogenesis of cortical glutamatergic neurons from murine ESCs.
    F1000Res. 2013 Feb 07;2:35 PMID: 24358889
  63. The genetic variation of RELN expression in schizophrenia and bipolar disorder.
    PLoS One. 2011;6(5):e19955 PMID: 21603580
Article Info
Journal
Cell
Abbr.
Cell
ISSN
1097-4172
DOI
10.1016/j.cell.2014.11.035
Email
[email protected]
[email protected]
Published
2014-12-18
Pages
1511-23
Language
English
Region
United States
NLM ID
0413066
PMCID
PMC4390143
Subset
IM
Grants
NIMH NIH HHS · R01 MH094714 · United States
NIGMS NIH HHS · T32 GM008042 · United States
NIMH NIH HHS · 5R37MH060233 · United States
NHGRI NIH HHS · U01 HG001715 · United States
NIMH NIH HHS · R37 MH060233 · United States
NHGRI NIH HHS · P50 HG004233 · United States
Canadian Institutes of Health Research · Canada
NIMH NIH HHS · 5R01MH094714 · United States
NHGRI NIH HHS · U01HG001715 · United States
NIMH NIH HHS · F30 MH099886 · United States
NHGRI NIH HHS · R01 HG003224 · United States
Databases
BioProject
PRJNA268211
GEO
GSE64018
Corrections
CommentIn
PMID: 25535247
External Links
PubMed source DOI: 10.1016/j.cell.2014.11.035 PMC Full Text View journal details
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