期刊
HUMAN MOLECULAR GENETICS
卷 22, 期 12, 页码 2376-2386出版社
OXFORD UNIV PRESS
DOI: 10.1093/hmg/ddt082
关键词
-
资金
- MRC Centre grant [G0700091]
- NIH [RO1 HG002995]
- Motor Neuron Disease Association (MNDA) UK
- Thierry Latran Foundation, France
- EU [259867]
- Medical Research Council, UK, Center Grant [G0700091]
- Medical Research Council [G0700091B] Funding Source: researchfish
- Motor Neurone Disease Association [Ramesh/Apr11/808-791] Funding Source: researchfish
- MRC [G0700091] Funding Source: UKRI
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.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据