Modification: FUS: Transgenic
Disease Relevance: Amyotrophic Lateral Sclerosis, Frontotemporal Dementia
Strain Name: B6.Cg-Tg(Prnp-FUS)17Ljh/J
Genetic Background: Construct microinjected into C57BL/6 x SJL)F2 hybrid embryos and founders bred to FVB for 4+ generations. Subsequently back-crossed at JAX to create a C57BL/6 congenic.
Availability: Congenic available through The Jackson Lab: Stock #020783; Cryopreserved
These transgenic mice overexpress wild-type human FUS within the nervous system via the mouse prion protein promoter (Prp) (Tibshirani et al., 2015). Hemizygous mice are viable, fertile, and apparently healthy with no overt neuropathology, motor impairment, or electromyographical abnormalities. However, despite this, half of hemizygotes die by ~203 days of age. The cause of this premature mortality is unknown. Death is preceded by an acute moribund state, characterized by poor feeding, leading to death within a week (The Jackson Laboratory website, Nov 2015).
This model was initially generated on a mixed background; however, a congenic is now available through The Jackson Laboratory. To date, only the hybrid line has been reported in the literature (Tibshirani et al., 2015).
On a mixed background, hemizygous mice carry about two copies of the FUS transgene. Expression of human FUS protein in brain and spinal cord is approximately equivalent to endogenous levels. FUS protein was predominantly nuclear. At five to six months of age, nuclear human FUS was present in spinal motor neurons, cortical neurons, deep cerebellar nuclei, lumbar spinal cord anterior horn cells, hippocampal neurons, and cerebellar granule cells. No cytoplasmic FUS inclusions were reported (The Jackson Laboratory website, Nov 2015).
Prior to becoming moribund, hemizygous mice displayed no overt signs of motor weakness or muscular abnormalities. Characterization of homozygous mice has not been reported to date (The Jackson Laboratory website, Nov 2015).
These mice overexpress wild-type human FUS. The transgene is driven by the mouse prion protein (PrP) promoter.
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
- Cytoplasmic Inclusions
- NMJ Abnormalities
- Cortical Neuron Loss
- Lower Motor Neuron Loss
- Muscle Atrophy
- Body Weight
Cortical Neuron Loss
Lower Motor Neuron Loss
Hemizygous mice die prematurely following a brief illness characterized by poor feeding. Mean survival of hemizygotes ~203 days.
- Tibshirani M, Tradewell ML, Mattina KR, Minotti S, Yang W, Zhou H, Strong MJ, Hayward LJ, Durham HD. Cytoplasmic sequestration of FUS/TLS associated with ALS alters histone marks through loss of nuclear protein arginine methyltransferase 1. Hum Mol Genet. 2015 Feb 1;24(3):773-86. Epub 2014 Sep 30 PubMed.
No Available Further Reading