Regulation of alternative splicing of human tau exon 10 by phosphorylation of splicing factors

Mol Cell Neurosci. 2001 Jul;18(1):80-90. doi: 10.1006/mcne.2001.1000.


Tau is a microtubule-associated protein whose transcript undergoes regulated splicing in the mammalian nervous system. Exon 10 of the gene is an alternatively spliced cassette that is adult-specific and encodes a microtubule-binding domain. Mutations increasing the inclusion of exon 10 result in the production of tau protein which predominantly contains four microtubule-binding repeats and were shown to cause frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17). Here we show that exon 10 usage is regulated by CDC2-like kinases CLK1, 2, 3, and 4 that phosphorylate serine-arginine-rich proteins, which in turn regulate pre-mRNA splicing. Cotransfection experiments suggest that CLKs achieve this effect by releasing specific proteins from nuclear storage sites. Our results show that changing pre-mRNA-processing pathways through phosphorylation could be a new therapeutic concept for tauopathies.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Alternative Splicing / physiology*
  • Amino Acid Sequence
  • Base Sequence
  • Cell Line
  • Cyclin-Dependent Kinase 5
  • Cyclin-Dependent Kinases / metabolism
  • Exons
  • Humans
  • Kidney / cytology
  • Microtubule-Associated Proteins / genetics
  • Molecular Sequence Data
  • Mutagenesis / physiology
  • Nuclear Proteins / genetics*
  • Nuclear Proteins / metabolism*
  • Phosphorylation
  • Point Mutation
  • Protein Serine-Threonine Kinases / metabolism
  • Protein-Tyrosine Kinases / metabolism
  • RNA Precursors / genetics
  • Transfection
  • tau Proteins / genetics*


  • MAPT protein, human
  • Microtubule-Associated Proteins
  • Nuclear Proteins
  • RNA Precursors
  • tau Proteins
  • Clk dual-specificity kinases
  • SRPK1 protein, human
  • Protein-Tyrosine Kinases
  • Cyclin-Dependent Kinase 5
  • Protein Serine-Threonine Kinases
  • CDK5 protein, human
  • Cyclin-Dependent Kinases