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Multilayered regulations of alternative splicing, NMD, and protein stability control temporal induction and tissue-specific expression of TRIM46 during axon formation

Author

Listed:
  • John K. Vuong

    (University of California, Riverside)

  • Volkan Ergin

    (University of California, Riverside)

  • Liang Chen

    (University of Southern California)

  • Sika Zheng

    (University of California, Riverside
    Center for RNA Biology and Medicine, University of California Riverside)

Abstract

The gene regulation underlying axon formation and its exclusiveness to neurons remains elusive. TRIM46 is postulated to determine axonal fate. We show Trim46 mRNA is expressed before axonogenesis, but TRIM46 protein level is inhibited by alternative splicing of two cassette exons coupled separately to stability controls of Trim46 mRNA and proteins, effectively inducing functional knockout of TRIM46 proteins. Exon 8 inclusion causes nonsense-mediated mRNA decay of Trim46 transcripts. PTBP2-mediated exon 10 skipping produces transcripts encoding unstable TRIM46 proteins. During axonogenesis, transcriptional activation, decreased exon 8 inclusion, and enhanced exon 10 inclusion converge to increase TRIM46 proteins, leading to its neural-specific expression. Genetic deletion of these exons alters TRIM46 protein levels and shows TRIM46 is instructive though not always required for AnkG localization nor a determinant of AnkG density. Therefore, two concurrently but independently regulated alternative exons orchestrate the temporal induction and tissue-specific expression of TRIM46 proteins to mediate axon formation.

Suggested Citation

  • John K. Vuong & Volkan Ergin & Liang Chen & Sika Zheng, 2022. "Multilayered regulations of alternative splicing, NMD, and protein stability control temporal induction and tissue-specific expression of TRIM46 during axon formation," Nature Communications, Nature, vol. 13(1), pages 1-18, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-29786-4
    DOI: 10.1038/s41467-022-29786-4
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    1. Hamdan Hamdan & Brian C. Lim & Tomohiro Torii & Abhijeet Joshi & Matthias Konning & Cameron Smith & Donna J. Palmer & Philip Ng & Christophe Leterrier & Juan A. Oses-Prieto & Alma L. Burlingame & Matt, 2020. "Mapping axon initial segment structure and function by multiplexed proximity biotinylation," Nature Communications, Nature, vol. 11(1), pages 1-17, December.
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