Tardbpl splicing rescues motor neuron and axonal development in a mutant tardbp zebrafish
- Authors
- Hewamadduma, C.A., Grierson, A.J., Ma, T.P., Pan, L., Moens, C.B., Ingham, P.W., Ramesh, T., and Shaw, P.J.
- ID
- ZDB-PUB-130309-7
- 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.
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.