Tra2 beta, SF2/ASF and SRp30c modulate the function of an exonic splicing enhancer in exon 10 of tau pre-mRNA

Genes Cells. 2004 Feb;9(2):121-30. doi: 10.1111/j.1356-9597.2004.00709.x.

Abstract

Some of mutations in the tau gene, which were found in frontotemporal dementia with Parkinsonism linked to chromosome 17 (FTDP-17), affect alternative splicing of its exon 10 which encodes one of four microtubule-binding motifs. To examine the molecular mechanisms responsible for aberrant splicing of the tau gene containing mutations linked to FTDP-17, we performed Exon trapping and binding assay using tau exon 10 pre-mRNA and nuclear extracts of neuroblastoma cell lines and in vitro splicing using dsx-substrate. We determined that 5' site of tau exon 10 (nucleotides 12-45) possesses exonic splicing enhancer (ESE) activities in vitro splicing and the FTDP-17-linked mutations affect the ESE activities and alter the splicing patterns of tau exon 10. Tra2 beta directly and ASF/SF2 indirectly associated with the ESE of wild tau exon 10. The binding amounts of these SR proteins to tau exon 10 bearing N279K mutation increased and they enhanced splicing the mutant tau exon 10. SRp30c also enhanced the splicing of tau exon 10. These results suggest that mutations in tau exon 10 that are linked to FTDP-17 affect the ESE activities by altering the binding of some SR proteins to its pre-mRNA.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alternative Splicing / genetics*
  • Animals
  • Cell Line
  • Enhancer Elements, Genetic
  • Exons / genetics
  • Humans
  • Microtubule-Associated Proteins / genetics
  • Microtubule-Associated Proteins / metabolism
  • Mutation, Missense
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism
  • Neuropeptides / genetics
  • Neuropeptides / metabolism
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism*
  • Phosphoproteins / genetics
  • Phosphoproteins / metabolism
  • Protein Binding
  • RNA Precursors / chemistry*
  • RNA Precursors / genetics
  • RNA Precursors / metabolism
  • RNA, Messenger / chemistry*
  • RNA, Messenger / metabolism
  • RNA-Binding Proteins / genetics
  • RNA-Binding Proteins / metabolism*
  • Sequence Deletion
  • Serine-Arginine Splicing Factors
  • tau Proteins / genetics*
  • tau Proteins / metabolism

Substances

  • Microtubule-Associated Proteins
  • Nerve Tissue Proteins
  • Neuropeptides
  • Nuclear Proteins
  • Phosphoproteins
  • RNA Precursors
  • RNA, Messenger
  • RNA-Binding Proteins
  • TRA2B protein, human
  • doublecortin protein
  • tau Proteins
  • Serine-Arginine Splicing Factors