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

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.This work was supported by the 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 B