Neuronal-specific microexon splicing of TAF1 mRNA is directly regulated by SRRM4/nSR100

RNA Biol. 2020 Jan;17(1):62-74. doi: 10.1080/15476286.2019.1667214. Epub 2019 Sep 27.

Abstract

Neuronal microexons represent the most highly conserved class of alternative splicing events and their timed expression shapes neuronal biology, including neuronal commitment and differentiation. The six-nt microexon 34' is included in the neuronal form of TAF1 mRNA, which encodes the largest subunit of the basal transcription factor TFIID. In this study, we investigate the tissue distribution of TAF1-34' mRNA and protein and the mechanism responsible for its neuronal-specific splicing. Using isoform-specific RNA probes and antibodies, we observe that canonical TAF1 and TAF1-34' have different distributions in the brain, which distinguish proliferating from post-mitotic neurons. Knockdown and ectopic expression experiments demonstrate that the neuronal-specific splicing factor SRRM4/nSR100 promotes the inclusion of microexon 34' into TAF1 mRNA, through the recognition of UGC sequences in the poly-pyrimidine tract upstream of the regulated microexon. These results show that SRRM4 regulates temporal and spatial expression of alternative TAF1 mRNAs to generate a neuronal-specific TFIID complex.

Keywords: Alternative mRNA splicing; TAF1; X-linked Dystonia Parkinsonism; basal transcription factors; microexons; neurogenesis; neuronal transcription.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Brain / metabolism
  • Cell Differentiation
  • Exons*
  • Gene Expression Regulation*
  • Histone Acetyltransferases / genetics*
  • Immunohistochemistry
  • Mice
  • Nerve Tissue Proteins / metabolism*
  • Neurogenesis / genetics
  • Neurons / cytology
  • Neurons / metabolism*
  • RNA Splicing*
  • RNA, Messenger / genetics*
  • TATA-Binding Protein Associated Factors / genetics*
  • Transcription Factor TFIID / genetics*

Substances

  • Nerve Tissue Proteins
  • RNA, Messenger
  • TATA-Binding Protein Associated Factors
  • Transcription Factor TFIID
  • nSR100 protein, mouse
  • Histone Acetyltransferases
  • TATA-binding protein associated factor 250 kDa

Grants and funding

This work was supported by the Collaborative Centre for X-linked Dystonia Parkinsonism (MT, JRC), The James and Pat Poitras Research Fund (AMG), The Saks Kavanaugh Foundation (AMG) and Stichting Parkinson Fonds (MPC, MV), and Deutsche Forschungsgemeinschaft SFB850 project B9 and SFB992 (MT). OS acknowledges support by Deutsche Forschungsgemeinschaft (GR 1748/6-1, SCHI 871/8-1, SCHI 871/9-1, SCHI 871/11-1, INST 39/900-1, and SFB850-Project Z1 (INST 39/766-3)), the Excellence Initiative of the German Federal and State Governments (EXC 294, BIOSS; GSC-4, Spemann Graduate School), and the German-Israel Foundation (Grant No. I-1444-201.2/2017). TR acknowledges support by Deutsche Forschungsgemeinschaft Re1584/6-2, SFB850 project B7.