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

Channa A A Hewamadduma, Andrew J Grierson, Taylur P Ma, Luyuan Pan, Cecilia B Moens, Philip W Ingham, Tennore Ramesh, Pamela J Shaw

Research output: Contribution to journalArticlepeer-review

31 Citations (SciVal)

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.

Original languageEnglish
Pages (from-to)2376-86
Number of pages11
JournalHuman Molecular Genetics
Volume22
Issue number12
DOIs
Publication statusPublished - 15 Jun 2013

Keywords

  • Amyotrophic Lateral Sclerosis/embryology
  • Animals
  • Axons/metabolism
  • DNA-Binding Proteins/genetics
  • Disease Models, Animal
  • Female
  • Gene Knockout Techniques
  • Humans
  • Male
  • Motor Neurons/metabolism
  • Mutation
  • RNA Splicing
  • Zebrafish/embryology
  • Zebrafish Proteins/genetics

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