Unknown

Dataset Information

0

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.

SUBMITTER: Hewamadduma CA 

PROVIDER: S-EPMC3658164 | biostudies-literature | 2013 Jun

REPOSITORIES: biostudies-literature

altmetric image

Publications

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

Hewamadduma Channa A A CA   Grierson Andrew J AJ   Ma Taylur P TP   Pan Luyuan L   Moens Cecilia B CB   Ingham Philip W PW   Ramesh Tennore T   Shaw Pamela J PJ  

Human molecular genetics 20130219 12


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 lac  ...[more]

Similar Datasets

| S-EPMC3121858 | biostudies-literature
| S-EPMC5581358 | biostudies-literature
| S-EPMC2974670 | biostudies-literature
| S-EPMC8190591 | biostudies-literature
2012-01-07 | E-MEXP-3402 | biostudies-arrayexpress
| S-EPMC6357263 | biostudies-literature
| S-EPMC7138241 | biostudies-literature
| S-EPMC9334911 | biostudies-literature
| S-EPMC7135881 | biostudies-literature
| S-EPMC5405110 | biostudies-literature