Research Models

Tardp_RRM2mut

Synonyms: RRM2mut

Species: Mouse
Genes: Tardbp
Mutations: Tardp F210I
Modification: Tardbp: Other
Disease Relevance: Frontotemporal Dementia, Amyotrophic Lateral Sclerosis
Strain Name: Tardbp F210I
Genetic Background: DBA/2J x C57BL/6J
Availability: Mice from original founders, on a hybrid DBA/2J x C57BL/6J background, are available from the RIKEN BioResource Center, BRC# GD000108.

Summary

RRM2mut mice harbor the p.F210I mutation within RNA recognition motif 2 (RRM2) of the endogenous mouse Tardp gene.  This line was generated after screening DNA archives from two large-scale chemical mutagenesis projects (Acevedo-Arozena et al., 2008; Gondo et al., 2010) for mutations in Tardbp. Mice express TDP-43 at physiological levels, under the control of its natural regulatory elements. Studies of cells and tissues derived from these mice revealed that the p.F210I mutation in TDP-43 results in a loss of splicing function.

When homozygous, the p.F210I mutation is embryonic lethal on both congenic C57BL/6J and mixed C57BL/6J x DBA/2J backgrounds, but embryos survive until at least embryonic day 18.5.  Heterozygous animals are viable and fertile.

Heterozygotes do not exhibit motor phenotypes, at least until 2 years of age—grip strength, muscle force, motor unit numbers, and motor neuron numbers are comparable to those of wild-type mice. No p62-or ubiquitin-positive inclusions were observed.

TDP-43 levels are similar in RRM2mut and wild-type mouse embryonic fibroblasts (MEFs). RNAseq revealed transcriptome-wide splicing changes in MEFs from RRM2mut homozygotes compared with wild-type MEFs, which paralleled the changes seen when shRNA was used to knock down TDP-43 expression in wild-type MEFs. Thirty-three cryptic exons, included exons that are normally constitutively repressed, were identified in homozygous RRM2mut MEFs.  iCLIP analysis performed on brains of embryonic RRM2mut homozygotes showed that p.F210I TDP-43 maintained normal RNA binding specificity.

Modification Details

DNA archives from two large-scale chemical mutagenesis projects (Acevedo-Arozena et al., 2008; Gondo et al., 2010) were screened for mutations in Tardbp. Founder mice were produced using the mutagenesis projects’ archived sperm (on a hybrid DBA/2J x C57BL/6J background), and backcrossed for at least five generations to place the Tardp mutation on congenic C57BL/6J and DBA/2J backgrounds and eliminate other potential mutations.

Availability

Mice from original founders, on a hybrid DBA/2J x C57BL/6J background, are available from the RIKEN BioResource Center, BRC# GD000108. C57BL/6J and DBA/2J congenic lines are in the process of being deposited at RIKEN and the European Mouse Mutant Archive (EMMA).

 

Phenotype Characterization

When visualized, these models will distributed over a 18 month timeline demarcated at the following intervals: 1mo, 3mo, 6mo, 9mo, 12mo, 15mo, 18mo+.

Absent

  • Motor Impairment
  • Lower Motor Neuron Loss
  • Cytoplasmic Inclusions
  • NMJ Abnormalities
  • Premature Death

No Data

  • Cortical Neuron Loss
  • Muscle Atrophy
  • Body Weight
  • Gliosis

Cortical Neuron Loss

No data.

Lower Motor Neuron Loss

Not observed at 2 years.

Cytoplasmic Inclusions

Not observed at 2 years.

Gliosis

No data.

NMJ Abnormalities

Not observed at 2 years.

Muscle Atrophy

No data.

Motor Impairment

Not observed at 2 years.

Body Weight

No data.

Premature Death

Homozygous mutation is embryonic lethal.

Last Updated: 17 Aug 2018

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References

Paper Citations

  1. . ENU-based gene-driven mutagenesis in the mouse: a next-generation gene-targeting system. Exp Anim. 2010;59(5):537-48. PubMed.

External Citations

  1. RIKEN BioResource Center
  2. RIKEN BioResource Center

Further Reading

No Available Further Reading