Mutations: Hexanucleotide repeat in C9ORF72
Modification: C9orf72: Transgenic
Disease Relevance: Amyotrophic Lateral Sclerosis, Frontotemporal Dementia
Strain Name: C57BL/6J-Tg(C9orf72_i3)112Lutzy/J
Genetic Background: C57BL/6J
Availability: The Jackson Lab: Stock# 023099; Live
This transgenic mouse expresses the repeat expansion (GGGGCC) within the C9ORF72 locus, which is associated with ALS and FTD. This model, generated by Cat Lutz at Jackson Labs and Robert Baloh at Cedars-Sinai, uses a bacterial artificial chromosome (BAC) to deliver the full-length C9ORF72 sequence with the disease-associated expansion (O’Rourke et al., 2015). The model contains multiple insertions of the transgene, each expressing ~100-1,000 hexanucleotide repeats. This entry specifically describes C9BACexp (line 112), which is well-characterized into advanced age and is available through the Jackson Lab.
Hemizygous C9BACexp line 112 mice are viable, fertile, and born in Mendelian ratios. They develop core pathologic features observed in C9ORF72 expansion carriers, including RNA foci in the nervous system. By three months of age, 40-80 percent of the cells throughout the brain exhibit sense and antisense foci. The distribution and frequency of the foci remain relatively stable as the animals age.
In addition to RNA foci, C9BACexp mice express poly-dipeptides translated from sense and antisense transcripts via repeat-associated non-ATG-dependent (RAN) translation. The mice express poly-glycine-proline peptides (poly-GP) in the brain and spinal cord. The poly-GP peptides are primarily soluble in six-month-old mice, but increasingly aggregate into inclusions as the mice age. Within the nervous system, poly-GP peptides were most abundant in the cerebellum and least abundant in in the spinal cord. Poly-glycine-alanine (poly-GA) peptides were also detected and displayed similar aggregation over time (Robert Baloh, personal communication, Dec 2015).
Despite the early and widespread appearance of RNA foci and poly-dipeptides, C9BACexp mice display very little neuropathology. Even at an advanced age (e.g., 18 months), they do not develop neurodegeneration, and likewise, gliosis, inflammation, and synapse loss are absent. Furthermore, there is no evidence of abnormal accumulation of TDP-43 or ubiquitin. One exception is that mild nucleolar dysfunction was observed in the form of dispersal of nucleolin from the nucleus.
Behaviorally, the mice are also appear remarkably normal. Even at an advanced age (18 months) they perform similarly to non-Tg controls in a battery of tests designed to assess motor performance (e.g., grip strength, Rotarod, open-field testing), social behavior (three-chamber test), and memory (Y-maze). To date, only behavioral data on male mice has been reported.
In summary, these mice model certain pathological aspects of disease (e.g., RNA foci, dipeptide repeats). The fact that they do not develop neurodegeneration or behavioral impairment suggests that RNA foci and poly-dipeptides alone are not sufficient to drive these phenotypes at levels seen in human tissue.
The BAC construct contains DNA isolated from an ALS patient carrying the C9 expansion (~800 repeats). The construct includes about 110kb upstream and 20kb downstream of the locus. The repeat sizes were comparable across tissues and brain regions, suggesting minimal somatic instability.
When visualized, these models will distributed over a 18 month timeline demarcated at the following intervals: 1mo, 3mo, 6mo, 9mo, 12mo, 15mo, 18mo+.
- Motor Impairment
- Cortical Neuron Loss
- Lower Motor Neuron Loss
- NMJ Abnormalities
- Muscle Atrophy
- Body Weight
- Premature Death
Cortical Neuron Loss
Lower Motor Neuron Loss
RNA foci throughout the nervous system starting at 3 months of age. Foci comprised of RNA transcripts in both the sense and antisense directions. Age-associated formation of dipeptide aggregates, e.g., poly-GP.
No increase in GFAP staining in the brain and spinal cord compared with non-Tg controls, even at 18 months of age.
No abnormalities in grip strength, Rotarod performance, or open-field testing at a young age (3 months) or advanced age (18 months), compared with non-Tg controls.
No abnormalities in body weight at a young age (3 months) or advanced age (18 months) compared with non-Tg controls.
- O'Rourke JG, Bogdanik L, Muhammad AK, Gendron TF, Kim KJ, Austin A, Cady J, Liu EY, Zarrow J, Grant S, Ho R, Bell S, Carmona S, Simpkinson M, Lall D, Wu K, Daughrity L, Dickson DW, Harms MB, Petrucelli L, Lee EB, Lutz CM, Baloh RH. C9orf72 BAC Transgenic Mice Display Typical Pathologic Features of ALS/FTD. Neuron. 2015 Dec 2;88(5):892-901. PubMed.