Non-nuclear Pool of Splicing Factor SFPQ Regulates Axonal Transcripts Required for Normal Motor Development.

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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. VIDEO ABSTRACT.

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Author and article information

Journal

Journal ID (iso-abbrev): Neuron

Title: Neuron

Publisher: Elsevier BV

ISSN (Electronic): 1097-4199

ISSN (Print): 0896-6273

Publication date (Electronic): Apr 19 2017

Volume: 94

Issue: 2

Affiliations

[1 ] Centre for Developmental Neurobiology and MRC CNDD, IoPPN, Guy's Campus, King's College London, London SE1 1UL, UK.

[2 ] Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology, and Neuroscience, King's College London, London SE5 8AF, UK.

[3 ] Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Macquarie University, Sydney, NSW 2109, Australia.

[4 ] Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Macquarie University, Sydney, NSW 2109, Australia; ANZAC Research Institute, University of Sydney, Concord Hospital, Sydney, NSW 2139, Australia.

[5 ] School of Anatomy, Physiology, and Human Biology, University of Western Australia, Crawley, WA 6009, Australia; Harry Perkins Institute for Medical Research, QEII Medical Centre, Nedlands, WA 6009, Australia; Centre for Medical Research, University of Western Australia, Crawley, WA 6009, Australia.

[6 ] School of Chemistry and Biochemistry, University of Western Australia, Crawley, WA 6009, Australia.

[7 ] Department of Developmental Biology, Stanford University School of Medicine, Stanford, CA 94305, USA.

[8 ] Centre for Developmental Neurobiology and MRC CNDD, IoPPN, Guy's Campus, King's College London, London SE1 1UL, UK. Electronic address: corinne.houart@kcl.ac.uk.

Article

Publisher Item ID: S0896-6273(17)30238-6

DOI: 10.1016/j.neuron.2017.03.026

PMC ID: 5405110

PubMed ID: 28392072

SO-VID: 99a5beb3-902a-4de8-81dc-25d413dd77bc

History

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

Data availability:

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

Non-nuclear Pool of Splicing Factor SFPQ Regulates Axonal Transcripts Required for Normal Motor Development.

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Most cited references 62

The Tol2kit: a multisite gateway-based construction kit for Tol2 transposon transgenesis constructs.

Analysis of the mouse transcriptome based on functional annotation of 60,770 full-length cDNAs.

Mutation in the tau gene in familial multiple system tauopathy with presenile dementia.

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