PMID- 15198676
OWN - NLM
STAT- MEDLINE
DCOM- 20040806
LR  - 20161124
IS  - 0022-3042 (Print)
IS  - 0022-3042 (Linking)
VI  - 90
IP  - 1
DP  - 2004 Jul
TI  - A minimal length between tau exon 10 and 11 is required for correct splicing of 
      exon 10.
PG  - 164-72
AB  - Mutations that stimulate exon 10 inclusion into the human tau mRNA cause 
      frontotemporal dementia with parkinsonism, associated with chromosome 17 
      (FTDP-17), and other tauopathies. This suggests that the ratio of exon 10 
      inclusion to exclusion in adult brain is one of the factors to determine 
      biological functions of the tau protein. To investigate the underlying splicing 
      mechanism and identify potential therapeutic targets for tauopathies, we 
      generated a series of mini-gene constructs with intron deletions from the full 
      length of tau exons 9-11 mini-gene construct. RT-PCR results demonstrate that 
      there is a minimum distance requirement between exon 10 and 11 for correct 
      splicing of the exon 10. In addition, SRp20, a member of serine-arginine (SR) 
      protein family of splicing factors was found to facilitate exclusion of exon 10 
      in a dosage-dependent manner. Significantly, SRp20 also induced exon 10 skipping 
      from pre-mRNAs containing mutations identified in FTDP-17 patients. Based on 
      those results, we generated a cell-based system to measure inclusion to exclusion 
      of exon 10 in the tau mRNA using the luciferase reporter. The firefly luciferase 
      was fused into exon 11 in frame, and a stop code was also created in exon 10. 
      Inclusion of exon 10 prevents luciferase expression, whereas exclusion of exon 10 
      generates luciferase activity. To minimize baseline luciferase expression, our 
      reporter construct also contains a FTDP-17 mutation that increases exon 10 
      inclusion. We demonstrate that the splicing pattern of our reporter construct 
      mimics that of endogenous tau gene. Co-transfection of SRp20 and SRp55, two SR 
      proteins that promote exon 10 exclusion, increases production of luciferase. We 
      conclude that this cell-based system can be used to identify biological 
      substances that modulate exon 10 splicing.
FAU - Yu, Qingming
AU  - Yu Q
AD  - Department of Medicine and Program in Neuroscience, University of Massachusetts 
      Medical School, Worcester, Massachusetts, USA.
FAU - Guo, Jun
AU  - Guo J
FAU - Zhou, Jianhua
AU  - Zhou J
LA  - eng
GR  - NS-45351/NS/NINDS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - England
TA  - J Neurochem
JT  - Journal of neurochemistry
JID - 2985190R
RN  - 0 (RNA Precursors)
RN  - 0 (RNA-Binding Proteins)
RN  - 0 (SRSF3 protein, human)
RN  - 0 (tau Proteins)
RN  - 170974-22-8 (Serine-Arginine Splicing Factors)
RN  - EC 1.13.12.- (Luciferases)
SB  - IM
MH  - Alternative Splicing
MH  - Animals
MH  - Cell Line
MH  - Exons/*genetics
MH  - Genes, Reporter
MH  - Humans
MH  - Introns/*genetics
MH  - Luciferases/biosynthesis/genetics
MH  - Mutation
MH  - RNA Precursors/*genetics/*metabolism
MH  - RNA Splicing/genetics/*physiology
MH  - RNA-Binding Proteins/genetics/metabolism
MH  - Serine-Arginine Splicing Factors
MH  - Tauopathies/genetics
MH  - Transfection
MH  - tau Proteins/*genetics
EDAT- 2004/06/17 05:00
MHDA- 2004/08/07 05:00
CRDT- 2004/06/17 05:00
PHST- 2004/06/17 05:00 [pubmed]
PHST- 2004/08/07 05:00 [medline]
PHST- 2004/06/17 05:00 [entrez]
AID - JNC2477 [pii]
AID - 10.1111/j.1471-4159.2004.02477.x [doi]
PST - ppublish
SO  - J Neurochem. 2004 Jul;90(1):164-72. doi: 10.1111/j.1471-4159.2004.02477.x.