Modification: TARDBP: Transgenic
Disease Relevance: Amyotrophic Lateral Sclerosis
Strain Name: B6SJL-Tg(Prnp-TARDBP)4Jlel/J
Genetic Background: Transgene injected into B6SJLF1 oocytes. Founders crossed with CD1 mice.
Availability: Status of original hybrid unknown. This model is available on a B6SJL background through The Jackson Lab: Stock# 016201; Cryopreserved
This model was among the first wave of TDP-43 transgenics (Stallings et al., 2010). It was originally created on a hybrid background (B6SJLF and CD1), and later developed into a B6SJL line distributed by The Jackson Lab (see below). The characterization data on this page refer to the original hybrid mice unless otherwise noted.
The mouse prion protein (Prp) promoter drives TDP-43 expression in this model. Hemizygous mice express intermediate levels of the human protein in the brain, spinal cord, and skeletal muscle, among other tissues.
Hemizygous mice develop motor impairments and muscle pathology. The motor impairment starts as muscle weakness in a hind limb that presents as an external rotation of one hind limb followed by bilateral weakness and low muscle tone. This phenotype is not fully penetrant; some mice show no evidence of muscle weakness even at six months of age.
An analysis of the quadriceps muscle showed myopathy, including variable muscle fiber size and disorganized muscle architecture. Myocytes accumulated TDP-43 protein (both nuclear and cytoplasmic), and they contained ubiquitin-positive inclusions. Although the Prp promoter primarily drives transgene expression in the CNS, relatively high TDP-43 expression was also observed in the skeletal muscle of these mice.
Hemizygous mice do not show overt neuronal loss in the brain or spinal cord. Their mean survival was 109 days. It was not reported whether the survial analysis included males, females, or both.
The transgene in this model encodes full-length, wild-type, human TDP-43 driven by the mouse prion protein (Prp) promoter. According to information on The Jackson Lab website, the transgene integrated on the X chromosome.
TDP-43 (WT) (hybrid) - This model on a hybrid B6SJL background is available through The Jackson Lab, Stock# 016201, cryopreserved. B6SJL-Tg(Prnp-TARDBP)4Jlel/J.
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
- Lower Motor Neuron Loss
- NMJ Abnormalities
Cortical Neuron Loss
Lower Motor Neuron Loss
Cytoplasmic ubiquitin-positive inclusions in skeletal muscle cells. Some TDP-43 inclusions too.
An analysis of the quadriceps muscle
, showed signs of myopathy including variable muscle fiber size and disorganization of the muscle architecture.
Progressive motor impairment starting with external rotation of one hind limb followed by bilateral weakness and low muscle tone. Variable penetrance of this phenotype.
Progressive weight loss.
The mean survival of hemizygous mice was 109 days (it is not clear if this value represents males, females, or both).
- Stallings NR, Puttaparthi K, Luther CM, Burns DK, Elliott JL. Progressive motor weakness in transgenic mice expressing human TDP-43. Neurobiol Dis. 2010 Nov;40(2):404-14. Epub 2010 Aug 2 PubMed.
No Available Further Reading