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
References
Paper Citations
- Gondo Y, Fukumura R, Murata T, Makino S. ENU-based gene-driven mutagenesis in the mouse: a next-generation gene-targeting system. Exp Anim. 2010;59(5):537-48. PubMed.
External Citations
Further Reading
No Available Further Reading
COMMENTS / QUESTIONS
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