Cytoplasmic pool of U1 spliceosome protein SNRNP70 shapes the axonal transcriptome and regulates motor connectivity

Nikolas Nikolaou, Patricia Gordon, Fursham Hamid, Richard Taylor, Joshua Lloyd-Jones, Eugene Makeyev, Corinne Houart

Research output: Contribution to journalArticlepeer-review

7 Citations (SciVal)

Abstract

Regulation of pre-mRNA splicing and polyadenylation plays a profound role in neurons by diversifying the proteome and modulating gene expression in response to physiological cues. Although most of the pre-mRNA processing is thought to occur in the nucleus, numerous splicing regulators are also found in neurites. Here, we show that U1-70K/SNRNP70, a component of the major spliceosome, localizes in RNA-associated granules in zebrafish axons. We identify the extra-nuclear SNRNP70 as an important regulator of motor axonal growth, nerve-dependent acetylcholine receptor (AChR) clustering, and neuromuscular synaptogenesis. This cytoplasmic pool has a protective role for a limited number of transcripts regulating their abundance and trafficking inside axons. Moreover, non-nuclear SNRNP70 regulates splice variants of transcripts such as agrin, thereby controlling synapse formation. Our results point to an unexpected, yet essential, function of non-nuclear SNRNP70 in axonal development, indicating a role of spliceosome proteins in cytoplasmic RNA metabolism during neuronal connectivity.

Original languageEnglish
Pages (from-to)5099-5115.e8
JournalCurrent Biology
Volume32
Issue number23
DOIs
Publication statusPublished - 5 Dec 2022

Bibliographical note

Funding Information:
We thank Prof. David Stanek for kindly giving us the human SNRNP70 construct, Prof. Martin Meyer for the HuC:Gal4 construct, Triona Fielding for technical support throughout the work, and Dr. Rachel Moore and Prof. Jon Clarke for assistance in using the Zeiss Airyscan confocal imaging system. We also thank the staff at King’s College London (Guy’s Campus) and the University of Bath fish facilities for their fish husbandry and care. This study was supported by the Biotechnology and Biological Sciences Research Council ( BB/P001599/1 to C.H. and BB/M007103/1 , BB/R001049/1 , and BB/V006258/1 to E.V.M.), the Wellcome Trust (Tech Dev. WT093389 and Investigator Award WT220861/Z to C.H.), and a University of Bath start-up package awarded to N.N.

Funding Information:
We thank Prof. David Stanek for kindly giving us the human SNRNP70 construct, Prof. Martin Meyer for the HuC:Gal4 construct, Triona Fielding for technical support throughout the work, and Dr. Rachel Moore and Prof. Jon Clarke for assistance in using the Zeiss Airyscan confocal imaging system. We also thank the staff at King's College London (Guy's Campus) and the University of Bath fish facilities for their fish husbandry and care. This study was supported by the Biotechnology and Biological Sciences Research Council (BB/P001599/1 to C.H. and BB/M007103/1, BB/R001049/1, and BB/V006258/1 to E.V.M.), the Wellcome Trust (Tech Dev. WT093389 and Investigator Award WT220861/Z to C.H.), and a University of Bath start-up package awarded to N.N. C.H. conceived the research project and secured funding. N.N. P.M.G. F.H. R.T. E.V.M. and C.H. designed the experiments. N.N. P.M.G. R.T. and J.L.-J. conducted the experiments. N.N. analyzed the data. F.H. performed the bioinformatic analysis of RNA-seq data. N.N. wrote the manuscript with input from all authors. The authors declare no competing interests

Publisher Copyright:
© 2022 The Author(s)

Keywords

  • Z+agrn
  • alternative splicing
  • mRNA processing
  • mRNA stability
  • mRNA transport
  • motor neurons
  • neurodegenerative diseases
  • neuromuscular junction
  • ribonucleoprotein complexes
  • synaptic connectivity

ASJC Scopus subject areas

  • Neuroscience(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

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