title: Non-nuclear Pool of Splicing Factor SFPQ Regulates Axonal Transcripts Required for Normal Motor Development.
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.
authors.affiliation: Centre for Developmental Neurobiology and MRC CNDD, IoPPN, Guy's Campus, King's College London, London SE1 1UL, UK.
authors.forename: Swapna
authors.initials: S
authors.lastname: Thomas-Jinu
authors.affiliation: Centre for Developmental Neurobiology and MRC CNDD, IoPPN, Guy's Campus, King's College London, London SE1 1UL, UK.
authors.forename: Patricia M
authors.initials: PM
authors.lastname: Gordon
authors.affiliation: Centre for Developmental Neurobiology and MRC CNDD, IoPPN, Guy's Campus, King's College London, London SE1 1UL, UK.
authors.forename: Triona
authors.initials: T
authors.lastname: Fielding
authors.affiliation: Centre for Developmental Neurobiology and MRC CNDD, IoPPN, Guy's Campus, King's College London, London SE1 1UL, UK.
authors.forename: Richard
authors.initials: R
authors.lastname: Taylor
authors.affiliation: Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology, and Neuroscience, King's College London, London SE5 8AF, UK.
authors.forename: Bradley N
authors.initials: BN
authors.lastname: Smith
authors.affiliation: Centre for Developmental Neurobiology and MRC CNDD, IoPPN, Guy's Campus, King's College London, London SE1 1UL, UK.
authors.forename: Victoria
authors.initials: V
authors.lastname: Snowden
authors.affiliation: Centre for Developmental Neurobiology and MRC CNDD, IoPPN, Guy's Campus, King's College London, London SE1 1UL, UK.
authors.forename: Eric
authors.initials: E
authors.lastname: Blanc
authors.affiliation: Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology, and Neuroscience, King's College London, London SE5 8AF, UK.
authors.forename: Caroline
authors.initials: C
authors.lastname: Vance
authors.affiliation: Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology, and Neuroscience, King's College London, London SE5 8AF, UK.
authors.forename: Simon
authors.initials: S
authors.lastname: Topp
authors.affiliation: Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology, and Neuroscience, King's College London, London SE5 8AF, UK.
authors.forename: Chun-Hao
authors.initials: CH
authors.lastname: Wong
authors.affiliation: Centre for Developmental Neurobiology and MRC CNDD, IoPPN, Guy's Campus, King's College London, London SE1 1UL, UK.
authors.forename: Holger
authors.initials: H
authors.lastname: Bielen
authors.affiliation: Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Macquarie University, Sydney, NSW 2109, Australia.
authors.forename: Kelly L
authors.initials: KL
authors.lastname: Williams
authors.affiliation: Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Macquarie University, Sydney, NSW 2109, Australia.
authors.forename: Emily P
authors.initials: EP
authors.lastname: McCann
authors.affiliation: 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.
authors.forename: Garth A
authors.initials: GA
authors.lastname: Nicholson
authors.affiliation: Centre for Developmental Neurobiology and MRC CNDD, IoPPN, Guy's Campus, King's College London, London SE1 1UL, UK.
authors.forename: Alejandro
authors.initials: A
authors.lastname: Pan-Vazquez
authors.affiliation: 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.
authors.forename: Archa H
authors.initials: AH
authors.lastname: Fox
authors.affiliation: School of Chemistry and Biochemistry, University of Western Australia, Crawley, WA 6009, Australia.
authors.forename: Charles S
authors.initials: CS
authors.lastname: Bond
authors.affiliation: Department of Developmental Biology, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: William S
authors.initials: WS
authors.lastname: Talbot
authors.affiliation: Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Macquarie University, Sydney, NSW 2109, Australia.
authors.forename: Ian P
authors.initials: IP
authors.lastname: Blair
authors.affiliation: Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology, and Neuroscience, King's College London, London SE5 8AF, UK.
authors.forename: Christopher E
authors.initials: CE
authors.lastname: Shaw
authors.affiliation: 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.
authors.forename: Corinne
authors.initials: C
authors.lastname: Houart
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000378:metabolism; D000818:Animals; D001369:Axons / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000378:metabolism; D006801:Humans; D051379:Mice; D009044:Motor Cortex / Q000254:growth & development; D009046:Motor Neurons / Q000378:metabolism*; D000072670:PTB-Associated Splicing Factor / Q000235:genetics / Q000378:metabolism*; D012326:RNA Splicing / Q000235:genetics*; D012333:RNA, Messenger / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000378:metabolism; D015027:Zebrafish
chemical_list: D004268:DNA-Binding Proteins; D000072670:PTB-Associated Splicing Factor; D012333:RNA, Messenger; D016601:RNA-Binding Proteins
keywords: PSF; RNA processing; RNA-binding protein; SFPQ; amyotrophic lateral sclerosis; axonogenesis; central nervous system; motor neurons; neurodegeneration; neurodevelopment