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

Abstract

SummaryRecent 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

Amyloid precursor protein, an androgen‐regulated gene, is targeted by RNA‐binding protein PSF/SFPQ in neuronal cells

“…Nuclear loss of the PSF protein in ALS transgenic mouse models and the spinal cord of human postmortem cases with sporadic ALS was observed, indicating that this event is a molecular hallmark of ALS (Luisier et al, 2018). Another report showed that PSF localized to the motor axons and promoted motor neuron differentiation ( Thomas-Jinu et al, 2017). Previous analysis of human AD/ FTD brain tissues and the dysregulated expression in a mouse model revealed the occurrence of a dysregulation in the PSF protein activity (Ke et al, 2012).…”

“…It would also be interesting to investigate whether estrogen receptor also has a role in the transcriptional regulation of APP-like AR or not. PSF encodes a protein involved in multiple roles such as RNA processing, transcriptional regulation and DNA repair contributing to axon viability in the neurons (Thomas-Jinu et al, 2017). PSF is localized within the nucleus of structures known as paraspeckles (Yarosh et al, 2015).…”

Human patientSFPQhomozygous mutation is found deleterious for brain and motor development in a zebrafish model

“…Human SFPQ lies in a region on chromosome 1p34-p36 already implicated in speech anomalies and language impairment and has been found to be mis-regulated in brains of patients with a variety of neurodegenerative disorders such as autism and dyslexia (Chang et al, 2015;Ke et al, 2012;Stamova et al, 2013;Tapia-Paez et al, 2008) . The SFPQ protein is conserved across species and plays a key role in neuronal development and network organization (Thomas-Jinu et al, 2017). The protein structure contains tandem RNA recognition motif domains, a NOPS domain, a coiled-coil region and an N-terminal proline/glutamine-rich low-complexity region (Passon et al, 2012).. More recently, loss of SFPQ function has been implicated as a risk factor for human neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS), fronto-temporal dementia (FTD) and Alzheimer's Disease (AD) (Ishigaki et al, 2017;Luisier et al, 2018;Takayama et al, 2019;Thomas-Jinu et al, 2017) in mouse, iPSC, and zebrafish models.…”

“…The SFPQ protein is conserved across species and plays a key role in neuronal development and network organization (Thomas-Jinu et al, 2017). The protein structure contains tandem RNA recognition motif domains, a NOPS domain, a coiled-coil region and an N-terminal proline/glutamine-rich low-complexity region (Passon et al, 2012).. More recently, loss of SFPQ function has been implicated as a risk factor for human neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS), fronto-temporal dementia (FTD) and Alzheimer's Disease (AD) (Ishigaki et al, 2017;Luisier et al, 2018;Takayama et al, 2019;Thomas-Jinu et al, 2017) in mouse, iPSC, and zebrafish models.…”

Expanding Axonal Transcriptome Brings New Functions for Axonally Synthesized Proteins in Health and Disease

“…SFPQ protein is needed for assembly of Bclw and lb2 mRNA granules for axonal localization (Cosker and others 2016). SFPQ is typically considered for its roles in transcription and splicing, but the cytosolic version of SFPQ is needed for motor development in zebrafish where the protein localizes to motor axons (Thomas-Jinu and others 2017). Nucleolin is similarly well characterized for nuclear functions (Tajrishi and others 2011), and its role in transport of Impβ1 emphasize that the neuron uses nuclear RBPs for multiple functions that include post-transcriptional regulation in the distal reaches of the cytoplasm.…”