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ZIRC
ZFIN ID: ZDB-PUB-130309-7
Tardbpl splicing rescues motor neuron and axonal development in a mutant tardbp zebrafish
Hewamadduma, C.A., Grierson, A.J., Ma, T.P., Pan, L., Moens, C.B., Ingham, P.W., Ramesh, T., and Shaw, P.J.
Date: 2013
Source: Human molecular genetics   22(12): 2376-86 (Journal)
Registered Authors: Hewamadduma, Channa A., Ingham, Philip, Ma, Taylur, Moens, Cecilia, Pan, Luyuan
Keywords: none
MeSH Terms:
  • Amyotrophic Lateral Sclerosis/embryology
  • Amyotrophic Lateral Sclerosis/genetics*
  • Amyotrophic Lateral Sclerosis/metabolism
  • Animals
  • Axons/metabolism*
  • DNA-Binding Proteins/genetics*
  • DNA-Binding Proteins/metabolism
  • Disease Models, Animal
  • Female
  • Gene Knockout Techniques
  • Humans
  • Male
  • Motor Neurons/metabolism*
  • Mutation
  • RNA Splicing*
  • Zebrafish/embryology
  • Zebrafish/genetics
  • Zebrafish/metabolism*
  • Zebrafish Proteins/genetics*
  • Zebrafish Proteins/metabolism
PubMed: 23427147 Full text @ Hum. Mol. Genet.
FIGURES
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.

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