Mutations: FUS ΔNLS
Modification: Fus: Knock-In
Disease Relevance: Amyotrophic Lateral Sclerosis
Strain Name: N/A
Genetic Background: C57Bl/6
FUS (Fused in Sarcoma) is a member of a family of RNA-binding proteins with roles in transcription, RNA processing, RNA transport, and translation. Mutations in FUS, many of which are clustered near the nuclear localization signal (NLS) at the C-terminus, are linked to familial cases of ALS. Additionally, truncation and frameshift mutations can result in the deletion of the NLS.
A targeting vector encoding exons 13 and 14 of Fus followed by three stop codons and a poly A signal was inserted between exons 12 and 13 of Fus (Scekic-Zahirovic et al., 2016). These elements are flanked by a pair of loxP sites. Insertion of this transgene results in the exclusion of exon 15, which contains the NLS, unless Cre-recombinase is expressed to excise the transgene. Because homozygous FusΔNLS/ΔNLS mice die shortly after birth, heterozygous FusΔNLS/+ males were used for histology and behavioral characterization (Scekic-Zahirovic et al., 2017).
In the spinal cords of FUSΔNLS/+ mice, Fus mRNA levels were slightly elevated. Mutant FUS was localized to the cytoplasm of ventral horn motor neurons, while wild-type Fus was predominantly nuclear. Additionally, ubiquitin pathology was observed in motor neurons, but p62 inclusions were not.
Mice expressing FusΔNLS began to exhibit motor abnormalities at 10 months, with irregular walking patterns and reduced hang time on the inverted grid test. Rotarod performance and grip strength were not altered. FusΔNLS/+ animals did not demonstrate weight loss nor did they develop paralysis by 22 months, when mice in the study were sacrificed.
Electromyography detected changes in electrical activity associated with muscle denervation at 22 months, but not at 10 months. These changes included fibrillation and fasciculation potentials in the gastrocnemius or tibialis anterior muscles and a reduction in compound muscle action potential amplitude. These changes were also associated with a loss of motor neurons from the lumbar spinal cord at 22 months. No change in motor neuron numbers were observed at 10 months. Oligodendrocyte numbers were slightly increased in the spinal cord white matter of FusΔNLS/+ animals compared to wild-type littermates.
When visualized, these models will distributed over a 18 month timeline demarcated at the following intervals: 1mo, 3mo, 6mo, 9mo, 12mo, 15mo, 18mo+.
- Body Weight
- Premature Death
- Cortical Neuron Loss
- Muscle Atrophy
Cortical Neuron Loss
Lower Motor Neuron Loss
Approximately 30% reduction of motor neuron numbers in the dorsal spinal cord.
Ubiquitin pathology was observed in motor neurons, but p62 inclusions were not.
Slight increase in oligodendrocytes in the spinal cord white matter.
Fibrillation and fasciculation potentials were observed in the gastrocnemius or tibialis anterior muscles. There was also a reduction in compound muscle action potential amplitude.
By 10 months, mice demonstrated irregular walking patterns and reduced hang time on the inverted grid test. No deficits in grip strength or rotarod performance. Paralysis was not observed.
By 22 months, no weight loss was observed.
Life span was not altered.
Last Updated: 12 May 2017
Research Models Citations
- Scekic-Zahirovic J, Sendscheid O, El Oussini H, Jambeau M, Sun Y, Mersmann S, Wagner M, Dieterlé S, Sinniger J, Dirrig-Grosch S, Drenner K, Birling MC, Qiu J, Zhou Y, Li H, Fu XD, Rouaux C, Shelkovnikova T, Witting A, Ludolph AC, Kiefer F, Storkebaum E, Lagier-Tourenne C, Dupuis L. Toxic gain of function from mutant FUS protein is crucial to trigger cell autonomous motor neuron loss. EMBO J. 2016 May 17;35(10):1077-97. Epub 2016 Mar 7 PubMed.
- Scekic-Zahirovic J, Oussini HE, Mersmann S, Drenner K, Wagner M, Sun Y, Allmeroth K, Dieterlé S, Sinniger J, Dirrig-Grosch S, René F, Dormann D, Haass C, Ludolph AC, Lagier-Tourenne C, Storkebaum E, Dupuis L. Motor neuron intrinsic and extrinsic mechanisms contribute to the pathogenesis of FUS-associated amyotrophic lateral sclerosis. Acta Neuropathol. 2017 Jun;133(6):887-906. Epub 2017 Feb 28 PubMed.
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