Mutations: FUS R521C
Modification: FUS: Transgenic
Disease Relevance: Amyotrophic Lateral Sclerosis, Frontotemporal Dementia
Strain Name: B6;SJL-Tg(Prnp-FUS*R521C)3313Ejh/J
Genetic Background: Transgene injected into B6SJL oocytes. Maintained on C57BL/6, therefore subsequent generations have a higher percentage of C57BL/6.
Availability: The Jackson Lab: Stock# 026406; Cryopreserved
At a young age, this transgenic mouse develops severe motor impairment and other ALS-related phenotypes. Notably, it develops robust neuronal loss in the spinal cord, denervation of neuromuscular junctions, and muscle atrophy. Phenotype development is swift—detectable within weeks of birth—and the mice decline rapidly. Most mice in the original N1F1 generation reached end-stage within three months (Qiu et al., 2014).
At one month of age, the mice express mutant FUS at levels approximately equal to endogenous FUS levels in the brain and spinal cord. The majority of the transgenic FUS-R521C protein in these mice is nuclear. Cytoplasmic protein is occasionally detected; however, less than 10 percent of spinal motor neurons contain cytoplasmic FUS inclusions. Endogenous FUS protein, but not transgenic protein, appears in dendrites as a punctate pattern. Similar to endogenous FUS, FUS-R521C protein is detected in astrocytes and oligodendrocytes, but not in microglia.
The mice develop prominent neuronal loss in the spinal cord. At birth, the number of spinal motor neurons is normal. However, by day 16, the number of ChAT-positive neurons in the anterior horn of the spinal cord is reduced by 20 percent. Degeneration continues, and by end stage, only about half of the neurons remain. The surviving motor neurons have reduced dendritic complexity, synaptic defects, and DNA damage. There is no detectable loss of cortical neurons; however, neurons in the sensorimotor cortex have reduced dendritic complexity and reduced synaptic density.
Despite modest transgene expression, FUS-R521C mice exhibit a variety of motor impairments from a young age, including spastic paraplegia and abnormal hindlimb clasping when lifted by the tail. They also have gait abnormalities, including reduced distance between their hind paws during walking. Performance on the Rotarod is poor.
The majority of mice in the original N1F1 generation reached end stage by postnatal day 100. Mice in subsequent generations (e.g., N2F2, N2F3), which have greater C57BL/6 contribution, live longer; about 40 percent reached end stage by postnatal day 200. Both male and female mice show similar disease phenotypes. Hemizygous males may be sterile, or at least have a much reduced breeding capacity (Eric Huang, personal communication, March 2016).
Data on this page refer to hemizygous mice. The phenotype of homozygous mice have not been reported.
The transgene in this model encodes human FUS with the R521C mutation near the C-terminus. It uses a flag-tagged construct driven by the Syrian hamster prion protein promoter.
When visualized, these models will distributed over a 18 month timeline demarcated at the following intervals: 1mo, 3mo, 6mo, 9mo, 12mo, 15mo, 18mo+.
- Cortical Neuron Loss
Cortical Neuron Loss
No detectable loss of cortical neurons; however, neurons in the sensorimotor cortex show reduced dendritic complexity and reduced synaptic density.
Lower Motor Neuron Loss
No detectable difference in spinal motor neurons at P0. At P16, about 20% loss of ChAT-positive neurons in the anterior horn of cervical spinal cord. At P30-P60, about 50% loss of anterior horn neurons. Remaining motor neurons show reduced dendritic complexity and synaptic density.
Less than 10% of spinal motor neurons have cytoplasmic FUS inclusions.
Prominent increase in microgliosis and astrogliosis in the anterior horn of the spinal cord by end stage.
Reduced innervation of neuromuscular junctions in the diaphragm.
The majority of mice have severe skeletal muscle atrophy in the hindlimb by end stage.
Early postnatal motor impairment, including abnormal hindlimb clasping when lifted by the tail, gait abnormalities, and impaired Rotarod performance.
Early postnatal growth is retarded, and the mice experience progressive loss of body weight.
The majority of mice in the N1F1 generation reached end stage and were sacrificed by postnatal day 100. Mice in subsequent generations live longer: about 40% reach end stage by postnatal day 200.
- Qiu H, Lee S, Shang Y, Wang WY, Au KF, Kamiya S, Barmada SJ, Finkbeiner S, Lui H, Carlton CE, Tang AA, Oldham MC, Wang H, Shorter J, Filiano AJ, Roberson ED, Tourtellotte WG, Chen B, Tsai LH, Huang EJ. ALS-associated mutation FUS-R521C causes DNA damage and RNA splicing defects. J Clin Invest. 2014 Mar 3;124(3):981-99. Epub 2014 Feb 10 PubMed.