A Nonsense Mutation in Mouse Tardbp Affects TDP43 Alternative Splicing Activity and Causes Limb-Clasping and Body Tone Defects

Mutations in TARDBP, encoding Tar DNA binding protein-43 (TDP43), cause amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Attempts to model TDP43 dysfunction in mice have used knockouts or transgenic overexpressors, which have revealed the difficulties of manipulating TDP43, who...

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Main Authors:	Ricketts, Thomas, McGoldrick, Philip, Fratta, Pietro, de Oliveira, Hugo M., Kent, Rosie, Phatak, Vinaya, Brandner, Sebastian, Blanco, Gonzalo, Greensmith, Linda, Acevedo-Arozena, Abraham, Fisher, Elizabeth M. C.
Format:	Online
Language:	English
Published:	Public Library of Science 2014
Online Access:	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3897576/

id	pubmed-3897576
recordtype	oai_dc
spelling	pubmed-38975762014-01-24 A Nonsense Mutation in Mouse Tardbp Affects TDP43 Alternative Splicing Activity and Causes Limb-Clasping and Body Tone Defects Ricketts, Thomas McGoldrick, Philip Fratta, Pietro de Oliveira, Hugo M. Kent, Rosie Phatak, Vinaya Brandner, Sebastian Blanco, Gonzalo Greensmith, Linda Acevedo-Arozena, Abraham Fisher, Elizabeth M. C. Research Article Mutations in TARDBP, encoding Tar DNA binding protein-43 (TDP43), cause amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Attempts to model TDP43 dysfunction in mice have used knockouts or transgenic overexpressors, which have revealed the difficulties of manipulating TDP43, whose level is tightly controlled by auto-regulation. In a complementary approach, to create useful mouse models for the dissection of TDP43 function and pathology, we have identified a nonsense mutation in the endogenous mouse Tardbp gene through screening an N-ethyl-N-nitrosourea (ENU) mutant mouse archive. The mutation is predicted to cause a Q101X truncation in TDP43. We have characterised TardbpQ101X mice to investigate this mutation in perturbing TDP43 biology at endogenous expression levels. We found the TardbpQ101X mutation is homozygous embryonic lethal, highlighting the importance of TDP43 in early development. Heterozygotes (Tardbp+/Q101X) have abnormal levels of mutant transcript, but we find no evidence of the truncated protein and mice have similar full-length TDP43 protein levels as wildtype littermates. Nevertheless, Tardbp+/Q101X mice have abnormal alternative splicing of downstream gene targets, and limb-clasp and body tone phenotypes. Thus the nonsense mutation in Tardbp causes a mild loss-of-function phenotype and behavioural assessment suggests underlying neurological abnormalities. Due to the role of TDP43 in ALS, we investigated potential interactions with another known causative gene, mutant superoxide dismutase 1 (SOD1). Tardbp+/Q101X mice were crossed with the SOD1G93Adl transgenic mouse model of ALS. Behavioural and physiological assessment did not reveal modifying effects on the progression of ALS-like symptoms in the double mutant progeny from this cross. In summary, the TardbpQ101X mutant mice are a useful tool for the dissection of TDP43 protein regulation, effects on splicing, embryonic development and neuromuscular phenotypes. These mice are freely available to the community. Public Library of Science 2014-01-21 /pmc/articles/PMC3897576/ /pubmed/24465814 http://dx.doi.org/10.1371/journal.pone.0085962 Text en © 2014 Ricketts et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
repository_type	Open Access Journal
institution_category	Foreign Institution
institution	US National Center for Biotechnology Information
building	NCBI PubMed
collection	Online Access
language	English
format	Online
author	Ricketts, Thomas McGoldrick, Philip Fratta, Pietro de Oliveira, Hugo M. Kent, Rosie Phatak, Vinaya Brandner, Sebastian Blanco, Gonzalo Greensmith, Linda Acevedo-Arozena, Abraham Fisher, Elizabeth M. C.
spellingShingle	Ricketts, Thomas McGoldrick, Philip Fratta, Pietro de Oliveira, Hugo M. Kent, Rosie Phatak, Vinaya Brandner, Sebastian Blanco, Gonzalo Greensmith, Linda Acevedo-Arozena, Abraham Fisher, Elizabeth M. C. A Nonsense Mutation in Mouse Tardbp Affects TDP43 Alternative Splicing Activity and Causes Limb-Clasping and Body Tone Defects
author_facet	Ricketts, Thomas McGoldrick, Philip Fratta, Pietro de Oliveira, Hugo M. Kent, Rosie Phatak, Vinaya Brandner, Sebastian Blanco, Gonzalo Greensmith, Linda Acevedo-Arozena, Abraham Fisher, Elizabeth M. C.
author_sort	Ricketts, Thomas
title	A Nonsense Mutation in Mouse Tardbp Affects TDP43 Alternative Splicing Activity and Causes Limb-Clasping and Body Tone Defects
title_short	A Nonsense Mutation in Mouse Tardbp Affects TDP43 Alternative Splicing Activity and Causes Limb-Clasping and Body Tone Defects
title_full	A Nonsense Mutation in Mouse Tardbp Affects TDP43 Alternative Splicing Activity and Causes Limb-Clasping and Body Tone Defects
title_fullStr	A Nonsense Mutation in Mouse Tardbp Affects TDP43 Alternative Splicing Activity and Causes Limb-Clasping and Body Tone Defects
title_full_unstemmed	A Nonsense Mutation in Mouse Tardbp Affects TDP43 Alternative Splicing Activity and Causes Limb-Clasping and Body Tone Defects
title_sort	nonsense mutation in mouse tardbp affects tdp43 alternative splicing activity and causes limb-clasping and body tone defects
description	Mutations in TARDBP, encoding Tar DNA binding protein-43 (TDP43), cause amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Attempts to model TDP43 dysfunction in mice have used knockouts or transgenic overexpressors, which have revealed the difficulties of manipulating TDP43, whose level is tightly controlled by auto-regulation. In a complementary approach, to create useful mouse models for the dissection of TDP43 function and pathology, we have identified a nonsense mutation in the endogenous mouse Tardbp gene through screening an N-ethyl-N-nitrosourea (ENU) mutant mouse archive. The mutation is predicted to cause a Q101X truncation in TDP43. We have characterised TardbpQ101X mice to investigate this mutation in perturbing TDP43 biology at endogenous expression levels. We found the TardbpQ101X mutation is homozygous embryonic lethal, highlighting the importance of TDP43 in early development. Heterozygotes (Tardbp+/Q101X) have abnormal levels of mutant transcript, but we find no evidence of the truncated protein and mice have similar full-length TDP43 protein levels as wildtype littermates. Nevertheless, Tardbp+/Q101X mice have abnormal alternative splicing of downstream gene targets, and limb-clasp and body tone phenotypes. Thus the nonsense mutation in Tardbp causes a mild loss-of-function phenotype and behavioural assessment suggests underlying neurological abnormalities. Due to the role of TDP43 in ALS, we investigated potential interactions with another known causative gene, mutant superoxide dismutase 1 (SOD1). Tardbp+/Q101X mice were crossed with the SOD1G93Adl transgenic mouse model of ALS. Behavioural and physiological assessment did not reveal modifying effects on the progression of ALS-like symptoms in the double mutant progeny from this cross. In summary, the TardbpQ101X mutant mice are a useful tool for the dissection of TDP43 protein regulation, effects on splicing, embryonic development and neuromuscular phenotypes. These mice are freely available to the community.
publisher	Public Library of Science
publishDate	2014
url	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3897576/
_version_	1612049537219690496

A Nonsense Mutation in Mouse Tardbp Affects TDP43 Alternative Splicing Activity and Causes Limb-Clasping and Body Tone Defects

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