Non-nuclear pool of splicing factor SFPQ regulates axonal transcripts required for normal motor development

Swapna Thomas-Jinu, Patricia M. Gordon, Triona Fielding, Richard Taylor, Bradley N. Smith, Victoria Snowden, Eric Blanc, Caroline Vance, Simon Topp, Chun Hao Wong, Holger Bielen, Kelly L. Williams, Emily P. McCann, Garth A. Nicholson, Alejandro Pan-Vazquez, Archa H. Fox, Charles S. Bond, William S. Talbot, Ian P. Blair, Christopher E. Shaw & 1 others Corinne Houart

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Abstract

Recent progress revealed the complexity of RNA processing and its association to human disorders. Here, we unveil a new facet of this complexity. Complete loss of function of the ubiquitous splicing factor SFPQ affects zebrafish motoneuron differentiation cell autonomously. In addition to its nuclear localization, the protein unexpectedly localizes to motor axons. The cytosolic version of SFPQ abolishes motor axonal defects, rescuing key transcripts, and restores motility in the paralyzed sfpq null mutants, indicating a non-nuclear processing role in motor axons. Novel variants affecting the conserved coiled-coil domain, so far exclusively found in fALS exomes, specifically affect the ability of SFPQ to localize in axons. They broadly rescue morphology and motility in the zebrafish mutant, but alter motor axon morphology, demonstrating functional requirement for axonal SFPQ. Altogether, we uncover the axonal function of the splicing factor SFPQ in motor development and highlight the importance of the coiled-coil domain in this process.

Original languageEnglish
Pages (from-to)322-336
Number of pages15
JournalNeuron
Volume94
Issue number2
DOIs
Publication statusPublished - 19 Apr 2017

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Bibliographical note

Copyright the Author(s) 2017. Version archived for private and non-commercial use with the permission of the author/s and according to publisher conditions. For further rights please contact the publisher.

Erratum: (Neuron 94, 322–336; April 19, 2017) As a result of an author oversight in the originally published version of this article, the first name of author Kelly L. Williams was written as “Katherine.” This error has now been corrected in the article online. The authors apologize for the error.

Keywords

  • amyotrophic lateral sclerosis
  • axonogenesis
  • central nervous system
  • motor neurons
  • neurodegeneration
  • neurodevelopment
  • PSF
  • RNA processing
  • RNA-binding protein
  • SFPQ

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