title: The Neuronal Splicing Factor Nova Co-Localizes with Target RNAs in the Dendrite.
abstract: Nova proteins are neuron-specific RNA binding proteins targeted by autoantibodies in a disorder manifest by failure of motor inhibition, and they regulate splicing and alternative 3' processing. Nova regulates splicing of RNAs encoding synaptic proteins, including the inhibitory glycine receptor alpha2 subunit (GlyRalpha2), and binds to others, including the GIRK2 channel. We found that Nova harbors functional NES and NLS elements, shuttles between the nucleus and cytoplasm, and that 50% of the protein localizes to the soma-dendritic compartment. Immunofluoresence and EM analysis of spinal cord motor neurons demonstrated that Nova co-localizes beneath synaptic contacts in dendrites with the same RNA, GlyRalpha2, whose splicing it regulates in the nucleus. HITS-CLIP identified intronic and 3' UTR sites where Nova binds to GlyRalpha2 and GIRK2 transcripts in the brain. This led directly to the identification of a 3' UTR localization element that mediates Nova-dependent localization of GIRK2 in primary neurons. These data demonstrate that HITS-CLIP can identify functional RNA localization elements, and they suggest new links between the regulation of nuclear RNA processing and mRNA localization.
authors.affiliation: Biologie Cellulaire de la Synapse Normale et Pathologique, Institut National de la Santé et de la Recherche Médicale, Ecole Normale Supérieure Paris, France.
authors.forename: Claudia
authors.initials: C
authors.lastname: Racca
authors.forename: Alejandra
authors.initials: A
authors.lastname: Gardiol
authors.forename: Taesun
authors.initials: T
authors.lastname: Eom
authors.forename: Jernej
authors.initials: J
authors.lastname: Ule
authors.forename: Antoine
authors.initials: A
authors.lastname: Triller
authors.forename: Robert B
authors.initials: RB
authors.lastname: Darnell
references.citation: Proc Natl Acad Sci U S A. 2009 Mar 3;106(9):3513-8
references.pmid: 19221030
references.citation: Annu Rev Neurosci. 2001;24:299-325
references.pmid: 11283313
references.citation: Neuroscience. 1991;43(2-3):381-95
references.pmid: 1656320
references.citation: Cell. 2005 Oct 7;123(1):105-18
references.pmid: 16213216
references.citation: Dev Cell. 2003 Jan;4(1):41-51
references.pmid: 12530962
references.citation: Curr Opin Cell Biol. 2008 Apr;20(2):144-9
references.pmid: 18378131
references.citation: Proc Natl Acad Sci U S A. 1998 Oct 27;95(22):13254-9
references.pmid: 9789075
references.citation: J Cell Biol. 1985 Aug;101(2):683-8
references.pmid: 2991304
references.citation: Proc Natl Acad Sci U S A. 1979 Nov;76(11):5977-81
references.pmid: 392511
references.citation: Cell. 1991 Apr 19;65(2):241-8
references.pmid: 2015625
references.citation: Nature. 2004 Feb 19;427(6976):753-7
references.pmid: 14973490
references.citation: Proc Natl Acad Sci U S A. 2000 Jun 6;97(12):6350-5
references.pmid: 10829067
references.citation: Neuron. 2000 Feb;25(2):359-71
references.pmid: 10719891
references.citation: Proc Natl Acad Sci U S A. 1999 Dec 21;96(26):14937-42
references.pmid: 10611316
references.citation: Neuroscience. 1998 Jun;84(4):997-1012
references.pmid: 9578391
references.citation: Cell. 2006 Jan 13;124(1):191-205
references.pmid: 16413491
references.citation: J Neurosci. 2006 Jul 5;26(27):7143-6
references.pmid: 16822969
references.citation: Nature. 2008 Nov 27;456(7221):464-9
references.pmid: 18978773
references.citation: Cell. 2009 Feb 20;136(4):719-30
references.pmid: 19239891
references.citation: Cell. 2000 Feb 4;100(3):323-32
references.pmid: 10676814
references.citation: Annu Rev Cell Dev Biol. 2001;17:569-614
references.pmid: 11687499
references.citation: Nature. 1992 Feb 20;355(6362):730-2
references.pmid: 1371331
references.citation: J Neurosci. 1997 Mar 1;17(5):1691-700
references.pmid: 9030628
references.citation: Science. 2003 Nov 14;302(5648):1212-5
references.pmid: 14615540
references.citation: J Cell Biol. 2004 Apr 26;165(2):203-11
references.pmid: 15096527
references.citation: EMBO J. 2007 Aug 22;26(16):3729-36
references.pmid: 17660744
references.citation: EMBO J. 1991 Sep;10(9):2401-9
references.pmid: 1651228
references.citation: Nat Rev Neurosci. 2001 Apr;2(4):240-50
references.pmid: 11283747
references.citation: EMBO J. 2005 Apr 20;24(8):1608-20
references.pmid: 15933722
references.citation: J Neurosci. 1999 Jan 1;19(1):168-79
references.pmid: 9870948
references.citation: Semin Oncol. 2006 Jun;33(3):270-98
references.pmid: 16769417
references.citation: FEBS Lett. 1991 May 20;283(1):73-7
references.pmid: 1645300
references.citation: Results Probl Cell Differ. 2001;34:41-56
references.pmid: 11288678
references.citation: Mol Cell. 2001 Dec;8(6):1351-61
references.pmid: 11779509
references.citation: Nature. 2006 Nov 30;444(7119):580-6
references.pmid: 17065982
references.citation: Nat Struct Mol Biol. 2009 Oct;16(10):1056-62
references.pmid: 19734899
references.citation: Neuron. 2003 Oct 30;40(3):581-94
references.pmid: 14642281
references.citation: Curr Biol. 2002 Jan 22;12(2):R50-2
references.pmid: 11818077
references.citation: Brain Res. 1986 Mar 26;369(1-2):316-20
references.pmid: 3008938
references.citation: Genes Dev. 2000 May 1;14(9):1098-108
references.pmid: 10809668
references.citation: Trends Biochem Sci. 2007 Jun;32(6):279-85
references.pmid: 17481902
references.citation: J Cell Biol. 1983 May;96(5):1337-54
references.pmid: 6404910
references.citation: Mol Cell Biol. 2003 Jul;23(13):4687-700
references.pmid: 12808107
references.citation: J Cell Biol. 1987 Apr;104(4):947-56
references.pmid: 3031086
references.citation: Annu Rev Neurosci. 2001;24:239-62
references.pmid: 11283311
references.citation: Mol Cell. 2007 Nov 9;28(3):359-70
references.pmid: 17996701
references.citation: Neuron. 2008 Oct 23;60(2):201-14
references.pmid: 18957214
references.citation: Nat Rev Genet. 2010 Jan;11(1):75-87
references.pmid: 20019688
references.citation: Proc Natl Acad Sci U S A. 1984 Nov;81(22):7224-7
references.pmid: 6095276
references.citation: Nature. 2008 Nov 27;456(7221):470-6
references.pmid: 18978772
references.citation: J Neurosci. 2008 Nov 12;28(46):11760-7
references.pmid: 19005037
references.citation: Science. 2007 May 25;316(5828):1191-4
references.pmid: 17525339
references.citation: J Neurosci. 2003 Nov 12;23(32):10433-44
references.pmid: 14614102
references.citation: Semin Cell Dev Biol. 2007 Apr;18(2):186-93
references.pmid: 17459736
references.citation: J Neurosci. 1994 Jan;14(1):39-53
references.pmid: 8283246
references.citation: Nature. 1987 Nov 5-11;330(6143):25-6
references.pmid: 2823147
references.citation: Br J Pharmacol. 2004 Sep;143(1):19-26
references.pmid: 15302677
references.citation: Cell. 1986 May 9;45(3):407-15
references.pmid: 3698103
references.citation: Science. 1995 Sep 22;269(5231):1734-7
references.pmid: 7569904
references.citation: Mol Cell Biol. 1997 Jun;17(6):3194-201
references.pmid: 9154818
references.citation: Cell. 2006 Oct 6;127(1):49-58
references.pmid: 17018276
references.citation: Curr Opin Neurobiol. 2006 Feb;16(1):102-10
references.pmid: 16418001
references.citation: J Neurosci. 1996 Feb 1;16(3):1114-22
references.pmid: 8558240
references.citation: Neuron. 1993 Oct;11(4):657-72
references.pmid: 8398153
references.citation: Proc Natl Acad Sci U S A. 1979 Nov;76(11):5982-6
references.pmid: 392512
references.citation: Methods. 2005 Dec;37(4):376-86
references.pmid: 16314267
references.citation: J Cell Biol. 1997 Mar 24;136(6):1263-70
references.pmid: 9087442
references.citation: Cold Spring Harb Symp Quant Biol. 2006;71:321-7
references.pmid: 17381312
references.citation: Genes Dev. 2009 Jan 1;23(1):1-11
references.pmid: 19136621
references.citation: Nat Struct Mol Biol. 2008 Aug;15(8):768-74
references.pmid: 18679428
references.citation: Mol Cell. 2000 Sep;6(3):673-82
references.pmid: 11030346
references.citation: Neuron. 1990 Dec;5(6):867-73
references.pmid: 2176511
references.citation: Curr Opin Cell Biol. 1992 Dec;4(6):975-8
references.pmid: 1485968
references.citation: N Engl J Med. 2003 Oct 16;349(16):1543-54
references.pmid: 14561798
references.citation: J Cell Biol. 2002 Jan 7;156(1):41-51
references.pmid: 11781334
references.citation: Nature. 2004 Apr 29;428(6986):959-63
references.pmid: 15118729
references.citation: Science. 2009 Nov 27;326(5957):1212-6
references.pmid: 19965463
references.citation: Nat Genet. 2005 Aug;37(8):844-52
references.pmid: 16041372
references.citation: Nat Rev Mol Cell Biol. 2005 May;6(5):363-75
references.pmid: 15852043
references.citation: Curr Biol. 2001 Oct 30;11(21):1666-74
references.pmid: 11696323
references.citation: Methods Mol Biol. 2008;488:85-98
references.pmid: 18982285