title: Tardbpl splicing rescues motor neuron and axonal development in a mutant tardbp zebrafish.
abstract: Mutations in the transactive response DNA binding protein-43 (TARDBP/TDP-43) gene, which regulates transcription and splicing, causes a familial form of amyotrophic lateral sclerosis (ALS). Here, we characterize and report the first tardbp mutation in zebrafish, which introduces a premature stop codon (Y220X), eliminating expression of the Tardbp protein. Another TARDBP ortholog, tardbpl, in zebrafish is shown to encode a Tardbp-like protein which is truncated compared with Tardbp itself and lacks part of the C-terminal glycine-rich domain (GRD). Here, we show that tardbp mutation leads to the generation of a novel tardbpl splice form (tardbpl-FL) capable of making a full-length Tardbp protein (Tardbpl-FL), which compensates for the loss of Tardbp. This finding provides a novel in vivo model to study TDP-43-mediated splicing regulation. Additionally, we show that elimination of both zebrafish TARDBP orthologs results in a severe motor phenotype with shortened motor axons, locomotion defects and death at around 10 days post fertilization. The Tardbp/Tardbpl knockout model generated in this study provides an excellent in vivo system to study the role of the functional loss of Tardbp and its involvement in ALS pathogenesis.
authors: Department of Neuroscience, Sheffield Institute for Translational Neuroscience, University of Sheffield, 385A, Glossop Road, Sheffield S10 2HQ, UK.
authors: Channa A A
authors: CA
authors: Hewamadduma
authors: Andrew J
authors: AJ
authors: Grierson
authors: Taylur P
authors: TP
authors: Ma
authors: Luyuan
authors: L
authors: Pan
authors: Cecilia B
authors: CB
authors: Moens
authors: Philip W
authors: PW
authors: Ingham
authors: Tennore
authors: T
authors: Ramesh
authors: Pamela J
authors: PJ
authors: Shaw
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000196:embryology / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D001369:Axons / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D055786:Gene Knockout Techniques; D006801:Humans; D008297:Male; D009046:Motor Neurons / Q000378:metabolism*; D009154:Mutation; D012326:RNA Splicing; D015027:Zebrafish / Q000196:embryology / Q000235:genetics / Q000378:metabolism*; D029961:Zebrafish Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: D004268:DNA-Binding Proteins; C585345:Tardbp protein, zebrafish; D029961:Zebrafish Proteins