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Tardbpl splicing rescues motor neuron and axonal development in a mutant tardbp zebrafish.

Human molecular genetics | Jun 15, 2013

http://www.ncbi.nlm.nih.gov/pubmed/23427147

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.

Pubmed ID: 23427147 RIS Download

Mesh terms: Amyotrophic Lateral Sclerosis | Animals | Axons | DNA-Binding Proteins | Disease Models, Animal | Female | Gene Knockout Techniques | Humans | Male | Motor Neurons | Mutation | RNA Splicing | Zebrafish | Zebrafish Proteins

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Associated grants

  • Agency: Medical Research Council, Id: G0700091
  • Agency: NICHD NIH HHS, Id: R01 HD076585
  • Agency: NHGRI NIH HHS, Id: R01 HG002995
  • Agency: Howard Hughes Medical Institute, Id:

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