B6(C3H)-Tardbp^m1H/J

Stock number: 019899
Research areas: Neurobiology Research, Research Tools

Description

Tardbp^Q101X ENU-induced mutant mice possess a nonsense mutation in exon 3 of the Tardbp gene. These mutant mice may be useful in studying the effects of TDP-43 protein regulation on the development of amyotrophic lateral sclerosis and frontotemporal dementia.

Detailed description

These Tardbp^Q101X ENU-induced mutant mice possess a nonsense mutation in exon 3 of the TAR DNA binding protein (Tardbp) gene. The Tardbp gene product, TDP-43, is a protein localized to the nucleus of nerve cells. Ubiquinated accumulations of mutant TDP-43 have been linked to the development of Lou Gehrig's disease (Amyotrophic lateral sclerosis; ALS) and frontotemporal dementia (FTD). Heterozygotes are viable and fertile, homozygotes are embryonic lethal by E6.5. The mutant allele produces a truncated transcript, although no truncated protein is detected. Interestingly, heterozygous mutant mice produce the same amount of wildtype TDP-43 protein as non-mutant-controls (the Tardbp gene is subject to autoregulation mechanisms), yet they exhibit a mild loss-of-function phenotype and behavioral abnormalities. Female mice display a hindlimb limb-clasp defect, with an average onset of 61 weeks, with no abnormal hindlimb neuromuscular function. Males and females also exhibit an abnormal, softer abdominal body tone.

Development

Following multidose N-ethyl-N-nitrosourea (ENU) treatments to induce mutations in founder male C57BL/6J mice, a forward genetic screen was utilized to identify mice with a mutation in the TAR DNA binding protein (Tardbp) gene. Males were bred with C3H/HeH females and sperm from F1 males was screened for mutations in Tardbp. A mutation was mapped with Sanger sequencing and a C to T transition in exon 3 of Tardbp resulting in a glutamine to Stop codon nonsense mutation (Q101X). Sperm from Tardbp^Q101X F1 males was used for in vitro fertilization of C57BL/6J oocytes. These Tardbp^Q101X mice were bred to C57BL/6J mice for at least 10 times prior to their arrival at The Jackson Laboratory, where they were further bred to C57BL/6J (Stock No. 000664) for at least one generation.

Allele

Symbol: Tardbp^m1H
Name: mutation 1, Harwell
MGI accession ID: MGI:5575763
Generation method: Chemically induced (ENU)
Attributes: Hypomorph
Synonyms: Tardbp^Q101X
Marker symbol: Tardbp
Marker name: TAR DNA binding protein
Marker synonyms: 1190002A23Rik; ALS10; Tdp43; TDP-43
Chromosome: 4
Strain of origin: C57BL/6J
Molecular note: ENU mutagenesis induced a C to T transition in exon 3 that results in the amino acid substitution of a glutamine to Stop codon nonsense mutation (Q101X).