Autoregulation of TDP-43 mRNA levels involves interplay between transcription, splicing, and alternative polyA site selection

Genes Dev. 2012 Aug 1;26(15):1679-84. doi: 10.1101/gad.194829.112.


TDP-43 is a critical RNA-binding factor associated with pre-mRNA splicing in mammals. Its expression is tightly autoregulated, with loss of this regulation implicated in human neuropathology. We demonstrate that TDP-43 overexpression in humans and mice activates a 3' untranslated region (UTR) intron, resulting in excision of the proximal polyA site (PAS) pA(1). This activates a cryptic PAS that prevents TDP-43 expression through a nuclear retention mechanism. Superimposed on this process, overexpression of TDP-43 blocks recognition of pA(1) by competing with CstF-64 for PAS binding. Overall, we uncover complex interplay between transcription, splicing, and 3' end processing to effect autoregulation of TDP-43.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alternative Splicing
  • Animals
  • Base Sequence
  • Cell Line
  • Cleavage Stimulation Factor / chemistry
  • Cleavage Stimulation Factor / metabolism
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism*
  • Homeostasis
  • Humans
  • Introns
  • Mice
  • Molecular Sequence Data
  • Poly A / metabolism*
  • Protein Binding
  • RNA Splice Sites
  • RNA Splicing*
  • RNA, Messenger / metabolism*
  • RNA-Binding Proteins / chemistry
  • RNA-Binding Proteins / metabolism
  • Transcription, Genetic*


  • CSTF2T protein, human
  • Cleavage Stimulation Factor
  • Cstf2t protein, mouse
  • DNA-Binding Proteins
  • RNA Splice Sites
  • RNA, Messenger
  • RNA-Binding Proteins
  • Poly A