title: Deficiency in the mRNA export mediator Gle1 impairs Schwann cell development in the zebrafish embryo.
abstract: GLE1 mutations cause lethal congenital contracture syndrome 1 (LCCS1), a severe autosomal recessive fetal motor neuron disease, and more recently have been associated with amyotrophic lateral sclerosis (ALS). The gene encodes a highly conserved protein with an essential role in mRNA export. The mechanism linking Gle1 function to motor neuron degeneration in humans has not been elucidated, but increasing evidence implicates abnormal RNA processing as a key event in the pathogenesis of several motor neuron diseases. Homozygous gle1(-/-) mutant zebrafish display various aspects of LCCS, showing severe developmental abnormalities including motor neuron arborization defects and embryonic lethality. A previous gene expression study on spinal cord from LCCS fetuses indicated that oligodendrocyte dysfunction may be an important factor in LCCS. We therefore set out to investigate the development of myelinating glia in gle1(-/-) mutant zebrafish embryos. While expression of myelin basic protein (mbp) in hindbrain oligodendrocytes appeared relatively normal, our studies revealed a prominent defect in Schwann cell precursor proliferation and differentiation in the posterior lateral line nerve. Other genes mutated in LCCS have important roles in Schwann cell development, thereby suggesting that Schwann cell deficits may be a common factor in LCCS pathogenesis. These findings illustrate the potential importance of glial cells such as myelinating Schwann cells in motor neuron diseases linked to RNA processing defects.
authors.affiliation: The Sheffield Institute for Translational Neuroscience, Department of Neuroscience, University of Sheffield, 385A Glossop Road, Sheffield S10 2HQ, UK.
authors.forename: A
authors.initials: A
authors.lastname: Seytanoglu
authors.affiliation: The Sheffield Institute for Translational Neuroscience, Department of Neuroscience, University of Sheffield, 385A Glossop Road, Sheffield S10 2HQ, UK.
authors.forename: N I
authors.initials: NI
authors.lastname: Alsomali
authors.affiliation: The Sheffield Institute for Translational Neuroscience, Department of Neuroscience, University of Sheffield, 385A Glossop Road, Sheffield S10 2HQ, UK.
authors.forename: C F
authors.initials: CF
authors.lastname: Valori
authors.affiliation: The Sheffield Institute for Translational Neuroscience, Department of Neuroscience, University of Sheffield, 385A Glossop Road, Sheffield S10 2HQ, UK.
authors.forename: A
authors.initials: A
authors.lastname: McGown
authors.affiliation: Bateson Centre, Department of Biomedical Science, University of Sheffield, Firth Court, Western Bank, Sheffield S10 2TN, UK.
authors.forename: H R
authors.initials: HR
authors.lastname: Kim
authors.affiliation: The Sheffield Institute for Translational Neuroscience, Department of Neuroscience, University of Sheffield, 385A Glossop Road, Sheffield S10 2HQ, UK.
authors.forename: K
authors.initials: K
authors.lastname: Ning
authors.affiliation: The Sheffield Institute for Translational Neuroscience, Department of Neuroscience, University of Sheffield, 385A Glossop Road, Sheffield S10 2HQ, UK.
authors.forename: T
authors.initials: T
authors.lastname: Ramesh
authors.affiliation: The Sheffield Institute for Translational Neuroscience, Department of Neuroscience, University of Sheffield, 385A Glossop Road, Sheffield S10 2HQ, UK; Department of Neurology, Royal Hallamshire Hospital, Sheffield Teaching Hospitals Foundation Trust, Glossop Road, Sheffield S10 2JF, UK.
authors.forename: B
authors.initials: B
authors.lastname: Sharrack
authors.affiliation: The Sheffield Institute for Translational Neuroscience, Department of Neuroscience, University of Sheffield, 385A Glossop Road, Sheffield S10 2HQ, UK; Bateson Centre, Department of Biomedical Science, University of Sheffield, Firth Court, Western Bank, Sheffield S10 2TN, UK.
authors.forename: J D
authors.initials: JD
authors.lastname: Wood
authors.affiliation: The Sheffield Institute for Translational Neuroscience, Department of Neuroscience, University of Sheffield, 385A Glossop Road, Sheffield S10 2HQ, UK; Faculty of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia. Electronic address: m.azzouz@sheffield.ac.uk.
authors.forename: M
authors.initials: M
authors.lastname: Azzouz
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D001176:Arthrogryposis; D002454:Cell Differentiation / Q000502:physiology; D049109:Cell Proliferation / Q000502:physiology; D005123:Eye / Q000196:embryology / Q000473:pathology; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D020287:In Situ Nick-End Labeling; D046529:Microscopy, Electron, Transmission; D009046:Motor Neurons / Q000473:pathology / Q000502:physiology; D004676:Myelin Basic Protein / Q000378:metabolism; D058953:Neural Stem Cells / Q000473:pathology / Q000502:physiology; D016601:RNA-Binding Proteins / Q000235:genetics; D012249:Rhombencephalon / Q000196:embryology / Q000473:pathology; D012583:Schwann Cells / Q000473:pathology / Q000502:physiology*; D016019:Survival Analysis; D015027:Zebrafish / Q000196:embryology*; D029961:Zebrafish Proteins / Q000172:deficiency* / Q000235:genetics
chemical_list: C571840:Gle1 protein, zebrafish; D004676:Myelin Basic Protein; D016601:RNA-Binding Proteins; D029961:Zebrafish Proteins
keywords: Schwann cell development; lethal congenital contracture syndrome 1; motor neuron; zebrafish model