title: Intragenic alternative splicing coordination is essential for Caenorhabditis elegans slo-1 gene function.
abstract: Alternative splicing is critical for diversifying eukaryotic proteomes, but the rules governing and coordinating splicing events among multiple alternate splice sites within individual genes are not well understood. We developed a quantitative PCR-based strategy to quantify the expression of the 12 transcripts encoded by the Caenorhabditis elegans slo-1 gene, containing three alternate splice sites. Using conditional probability-based models, we show that splicing events are coordinated across these sites. Further, we identify a point mutation in an intron adjacent to one alternate splice site that disrupts alternative splicing at all three sites. This mutation leads to aberrant synaptic transmission at the neuromuscular junction. In a genomic survey, we found that a UAAAUC element disrupted by this mutation is enriched in introns flanking alternate exons in genes with multiple alternate splice sites. These results establish that proper coordination of intragenic alternative splicing is essential for normal physiology of slo-1 in vivo and identify putative specialized cis-regulatory elements that regulate the coordination of intragenic alternative splicing.
authors.affiliation: Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Dominique A
authors.initials: DA
authors.lastname: Glauser
authors.forename: Brandon E
authors.initials: BE
authors.lastname: Johnson
authors.forename: Richard W
authors.initials: RW
authors.lastname: Aldrich
authors.forename: Miriam B
authors.initials: MB
authors.lastname: Goodman
mesh_terms: D000483:Alleles; D017398:Alternative Splicing; D000818:Animals; D001522:Behavior, Animal; D017173:Caenorhabditis elegans; D029742:Caenorhabditis elegans Proteins / Q000235:genetics* / Q000502:physiology*; D005091:Exons; D005786:Gene Expression Regulation; D023281:Genomics; D007438:Introns; D051036:Large-Conductance Calcium-Activated Potassium Channels / Q000235:genetics* / Q000378:metabolism / Q000502:physiology*; D008957:Models, Genetic; D009154:Mutation; D016133:Polymerase Chain Reaction; D022821:RNA Splice Sites
chemical_list: D029742:Caenorhabditis elegans Proteins; D051036:Large-Conductance Calcium-Activated Potassium Channels; D022821:RNA Splice Sites; C494845:slo-1 protein, C elegans
references.citation: Proc Natl Acad Sci U S A. 2011 Dec 20;108(51):20784-9
references.pmid: 22049343
references.citation: J Neurosci. 2003 Jul 23;23(16):6537-45
references.pmid: 12878695
references.citation: Proc Natl Acad Sci U S A. 2005 Dec 6;102(49):17870-6
references.pmid: 16306267
references.citation: Nucleic Acids Res. 2011 Jan;39(2):666-74
references.pmid: 20805248
references.citation: Nat Protoc. 2006;1(4):1772-7
references.pmid: 17487159
references.citation: Mol Cell. 2005 Aug 5;19(3):393-404
references.pmid: 16061185
references.citation: BMC Mol Biol. 2008 Jan 22;9:9
references.pmid: 18211699
references.citation: FEBS Lett. 2005 Aug 29;579(21):4856-60
references.pmid: 16102753
references.citation: Neuron. 2001 Dec 6;32(5):867-81
references.pmid: 11738032
references.citation: PLoS One. 2008 May 21;3(5):e2208
references.pmid: 18493300
references.citation: J Biol Chem. 1997 May 2;272(18):11710-7
references.pmid: 9115223
references.citation: Gene. 2005 Jan 3;344:1-20
references.pmid: 15656968
references.citation: Nat Genet. 2008 Dec;40(12):1413-5
references.pmid: 18978789
references.citation: PLoS Comput Biol. 2006 Jul 14;2(7):e86
references.pmid: 16839192
references.citation: BMC Dev Biol. 2006 Jul 27;6:37
references.pmid: 16872513
references.citation: Science. 2008 Aug 15;321(5891):956-60
references.pmid: 18599741
references.citation: J Biol Chem. 2005 Sep 30;280(39):33599-609
references.pmid: 16081418
references.citation: Cell. 2006 Jul 14;126(1):37-47
references.pmid: 16839875
references.citation: Annu Rev Physiol. 2009;71:19-36
references.pmid: 18694345
references.citation: J Biol Chem. 2008 Jan 18;283(3):1223-7
references.pmid: 18024427
references.citation: Mol Endocrinol. 1999 Oct;13(10):1728-37
references.pmid: 10517674
references.citation: J Biol Chem. 2008 Jan 18;283(3):1217-21
references.pmid: 18024429
references.citation: WormBook. 2006 Feb 11;:1-11
references.pmid: 18050451
references.citation: Nat Rev Mol Cell Biol. 2009 Nov;10(11):741-54
references.pmid: 19773805
references.citation: BMC Plant Biol. 2008 Feb 19;8:17
references.pmid: 18282305