Location of Repository

Functional coordination of alternative splicing in the mammalian central nervous system

By M. Fagnani, Y. Barash, C. Misquitta, Q. Pan, A.L. Saltzman, O. Shai, L. Lee, A. Rozenhek, N. Mohammad, S. Willaime-Morawek, T. Babak, W. Zhang, T.R. Hughes, D. van der Kooy, B.J. Frey and B.J. Blencowe

Abstract

BACKGROUND: Alternative splicing (AS) functions to expand proteomic complexity and plays numerous important roles in gene regulation. However, the extent to which AS coordinates functions in a cell and tissue type specific manner is not known. Moreover, the sequence code that underlies cell and tissue type specific regulation of AS is poorly understood. RESULTS: Using quantitative AS microarray profiling, we have identified a large number of widely expressed mouse genes that contain single or coordinated pairs of alternative exons that are spliced in a tissue regulated fashion. The majority of these AS events display differential regulation in central nervous system (CNS) tissues. Approximately half of the corresponding genes have neural specific functions and operate in common processes and interconnected pathways. Differential regulation of AS in the CNS tissues correlates strongly with a set of mostly new motifs that are predominantly located in the intron and constitutive exon sequences neighboring CNS-regulated alternative exons. Different subsets of these motifs are correlated with either increased inclusion or increased exclusion of alternative exons in CNS tissues, relative to the other profiled tissues. CONCLUSION: Our findings provide new evidence that specific cellular processes in the mammalian CNS are coordinated at the level of AS, and that a complex splicing code underlies CNS specific AS regulation. This code appears to comprise many new motifs, some of which are located in the constitutive exons neighboring regulated alternative exons. These data provide a basis for understanding the molecular mechanisms by which the tissue specific functions of widely expressed genes are coordinated at the level of AS

Topics: RC0321, QH426
Year: 2007
OAI identifier: oai:eprints.soton.ac.uk:66441
Provided by: e-Prints Soton

Suggested articles

Preview

Citations

  1. (2000). Alternative pre-mRNA splicing: the logic of combinatorial control. Trends Biochem Sci
  2. (2001). Alternative splicing: increasing diversity in the proteomic world. Trends Genet
  3. (2006). Alternative splicing: new insights from global analyses. Cell
  4. (2004). Analysis of alternative splicing with microarrays: successes and challenges. Genome Biol
  5. (2006). Artero R: The Muscleblind family of proteins: an emerging class of regulators of developmentally programmed alternative splicing. Differentiation
  6. (2005). Blencowe BJ: Alternative splicing of conserved exons is frequently species-specific in human and mouse. Trends Genet
  7. (2006). Blencowe BJ: Quantitative microarray profiling provides evidence against widespread coupling of alternative splicing with nonsense-mediated mRNA decay to control gene expression. Genes Dev
  8. (2004). CB: Variation in alternative splicing across human tissues. Genome Biol
  9. (2004). Chedotal A: RGM and its receptor neogenin regulate neuronal survival. Nat Cell Biol
  10. (2005). Conboy JG: The splicing regulatory element, UGCAUG, is phylogenetically and spatially conserved in introns that flank tissue-specific alternative exons. Nucleic Acids Res
  11. (2005). CW: Understanding alternative splicing: towards a cellular code. Nat Rev Mol Cell Biol
  12. (2003). DD: Genomewide survey of human alternative pre-mRNA splicing with exon junction microarrays. Science
  13. (2004). Detecting tissue-specific regulation of alternative splicing as a qualitative change in microarray data. Nucleic Acids Res
  14. (2000). DL: Cooperative assembly of an hnRNP complex induced by a tissue-specific homolog of polypyrimidine tract binding protein. Mol Cell Biol
  15. (2004). E, et al.: The functional landscape of mouse gene expression.
  16. (2005). Evolutionarily conserved elements in vertebrate, insect, worm, and yeast genomes. Genome Res
  17. (2001). Genome-wide detection of alternative splicing in expressed sequences of human genes.
  18. (2006). HB: Mammalian CELF/ Bruno-like RNA-binding proteins: molecular characteristics and biological functions. Biochimie
  19. (1997). HM: Mouse Neogenin, a DCC-like molecule, has four splice variants and is expressed widely in the adult mouse and during embryogenesis. Oncogene
  20. (2006). Inferring global levels of alternative splicing isoforms using a generative model of microarray data. Bioinformatics
  21. (2006). Intronic binding sites for hnRNP A/B and hnRNP F/ H proteins stimulate pre-mRNA splicing. PLoS Biol
  22. (2006). JA: Dual role of the exocyst in AMPA receptor targeting and insertion into the postsynaptic membrane.
  23. (2005). Jurisica I: Online predicted human interaction database. Bioinformatics
  24. (2005). Kawamoto S: Tissue-dependent isoforms of mammalian Fox-1 homologs are associated with tissue-specific splicing activities. Nucleic Acids Res
  25. (2005). Kornblihtt AR: A polar mechanism coordinates different regions of alternative splicing within a single gene. Mol Cell
  26. (2003). Mechanisms of alternative pre-messenger RNA splicing. Annu Rev Biochem
  27. (2001). N: A simple hyper-geometric approach for discovering putative transcription factor binding sites.
  28. (2004). Nogues G: Multiple links between transcription and splicing. RNA
  29. (2005). Nova regulates brain-specific splicing to shape the synapse. Nat Genet
  30. (2003). Osprey: a network visualization system. Genome Biol
  31. (1997). PJ: A neuron-specific splicing switch mediated by an array of pre-mRNA repressor sites: evidence of a regulatory role for the polypyrimidine tract binding protein and a brain-specific PTB counterpart. RNA
  32. (2007). R108.17 c o m m e n t r e v i e w s r e p o r t s r e f e r e e d r e s e a r c h d e p o s i t e d r e s e a r c h i n t e r a c t i o n s i n f o r m a t i o n Genome Biology
  33. (2006). RB: An RNA map predicting Novadependent splicing regulation. Nature
  34. (2000). RB: The tetranucleotide UCAY directs the specific recognition of RNA by the Nova K-homology 3 domain. Proc Natl Acad Sci USA
  35. (2004). Revealing global regulatory features of mammalian alternative splicing using a quantitative microarray platform. Mol Cell
  36. (1997). RH: Subunit structure of the mammalian exocyst complex. Proc Natl Acad Sci USA
  37. (2003). Ruegg MA: New insights into the roles of agrin.
  38. (2004). SE: The evolving roles of alternative splicing. Curr Opin Struct Biol
  39. (2005). Sequence conservation, relative isoform frequencies, and nonsense-mediated decay in evolutionarily conserved alternative splicing.
  40. (2005). Sex and the single splice. Cell
  41. (2003). Splicing regulation in Drosophila sex determination. Prog Mol Subcell Biol
  42. (2002). TA: Finding signals that regulate alternative splicing in the post-genomic era. Genome Biol
  43. (2004). The multiassembly problem: reconstructing multiple transcript isoforms from EST fragment mixtures. Genome Res
  44. (2006). Unusual intron conservation near tissue-regulated exons found by splicing microarrays. PLoS Comput Biol
  45. (2005). Use of minigene systems to dissect alternative splicing elements. Methods

To submit an update or takedown request for this paper, please submit an Update/Correction/Removal Request.