Prp-TDP43A315T transgenic mice express a mutant human TAR DNA binding protein cDNA harboring an amino acid substitution associated with familial ALS. Hemizygous mice develop a progressive and fatal neurodegenerative disease reminiscent of both ALS and frontotemporal lobar degeneration with ubiquitin aggregates. These transgenic mice may be useful in studying neuromuscular and neurodegenerative disorders such as ALS (Lou Gehrig's Disease) and frontotemporal lobar degeneration with ubiquitin aggregates.
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Robert H Baloh, Cedars Sinai Medical Center
Mice hemizygous for this Prp-TDP43A315T transgene are viable, fertile, and express a mutant human TAR DNA binding protein (TARDBP or TDP-43) cDNA harboring an N-terminal Flag tag and an A315T amino acid substitution that is associated with familial Amyotrophic Lateral Sclerosis (ALS). Expression is directed throughout the nervous system by mouse prion protein (PrP or Prnp) promoter/enhancer regions.
Hemizygous mice were originally published on a mixed C57BL/6;CBA genetic background and develop a progressive gait disorder around 3-4 months of age with death around 5 months of age. For hemizygous mice on a mixed C57BL/6;CBA genetic background, the donating investigator reports that, on average, males die almost one month earlier than females. Due to continued backcrossing to C57BL/6J at The Jackson Laboratory Repository, this strain is now fully congenic on a C57BL/6J background. Survival differences between male and female hemizygous mice are still observed. However, hemizygous males on a C57BL/6J genetic background have an average survival time of approximately 3.5 months (97 +/- 11 days); this is earlier lethality than hemizygous males on a mixed C57BL/6;CBA genetic background. On a C57BL/6J genetic background, hemizygous females live significantly longer than hemizygous males. In addition, male mice exhibit a progressive neurodegeneration in the myenteric plexus of the colon, which is characterized by reduced GI motility and contributes to the decreased lifespan observed in these mice. This phenotype is most severe in males on the C57BL/6J background.For more detailed information, please view graph of B6.Tg(Prnp-TARDBP*A315T)95Balo/J survival and data 2010-2012. [pdf] The intestinal dysmotility phenotype observed in these mice can be mitigated by the use of jellified food. Mice fed jellifed food survive and develop a progressive motor phenotype including gait abnormalities, denervated neuromuscular junctions, gastrocnemius muscle atrophy, and upper and lower motor axon loss (especially large axons). (Herdewyn et. al. Mol Neuro 9:24, 2014)
The progressive and fatal neurodegenerative disease phenotype of hemizygous mice is reminiscent of both ALS and frontotemporal lobar degeneration with ubiquitin aggregates (FTLD-U). Specifically, hemizygous mice accumulate pathologic aggregates of ubiquitinated proteins only in specific neuronal populations, including frontal cortex layer V pyramidal neurons and spinal motor neurons with activation of local astrocytes and microglia. Loss of both upper and lower motor neurons is also observed. TDP-43 aggregates are not reported in the cytoplasm. The donating investigator has not attempted to make homozygous mice.
In an attempt to offer alleles on well-characterized or multiple genetic backgrounds, alleles are frequently moved to a genetic background different from that on which an allele was first characterized. As the Prp-TDP43A315T transgenic mice were originally created on a mixed C57BL/6;CBA genetic background, it should be noted that the phenotype of these Prp-TDP43A315T transgenic mice on a C57BL/6-congenic background may vary greatly from that originally described. We will modify the strain description if necessary as published results become available.
A full-length human TAR DNA binding protein (TARDBP or TDP-43) cDNA sequence was modified to harbor an N-terminal Flag tag immediately after the start methionine and the A315T amino acid substitution associated with familial ALS. This Flag-TDP43A315T sequence was inserted between exon 2 and exon 3 of mouse prion protein (PrP or Prnp) gene at two unique XhoI sites in the Mo-Prp.Xho plasmid vector (ATCC#JHU-2). The resulting Prp-TDP43A315T transgene was microinjected into oocytes from hybrid C57BL/6J x CBA mice and a single founder mouse was bred with C57BL/6 wildtype mice to establish Prp-TDP43A315T founder line 95. These mice were then backcrossed to C57BL/6J inbred mice for approximately five generations (with black or agouti coat color) prior to sending agouti mice to The Jackson Laboratory Repository. Upon arrival, transgenic mice were bred with C57BL/6J inbred mice (Stock No. 000664) to establish the colony. A subsequent genome scan revealed this stock to be approximately 80% congenic to C57BL/6J. After this, hemizygous mice were additionally backcrossed to C57BL/6J inbred mice for multiple generations to make the mice fully congenic on the C57BL/6J genetic background.
|Expressed Gene||TARDBP, TAR DNA binding protein, human|
|Site of Expression|
|Allele Name||transgene insertion 95, Robert Baloh|
|Allele Type||Transgenic (Inserted expressed sequence, Humanized sequence)|
|Allele Synonym(s)||Prp-TDP43A315T; Prp-TDP43A315T; Prp-TDP43-A315T|
|Gene Symbol and Name||Tg(Prnp-TARDBP*A315T)95Balo, transgene insertion 95, Robert Baloh|
|Promoter||Prnp, prion protein, mouse, laboratory|
|Expressed Gene||TARDBP, TAR DNA binding protein, human|
|Strain of Origin||C57BL/6 x CBA|
|Molecular Note||The construct contains the full-length human TAR DNA binding protein (TARDBP or TDP-43) cDNA sequence that was modified to harbor an N-terminal Flag tag immediately after the start methionine and the A315T amino acid substitution associated with familial ALS inserted between exon 2 and exon 3 of mouse prion protein (PrP or Prnp) gene. A single Prp-TDP43A315T founder line was established (founder line 95) mapping to two close but distinct sites on Chr 9: Chr9:38,417,354 and Chr9:38,405,898 (coordinates from MGSC ver 37, mm9).|
|Mutations Made By|| |
Robert Baloh, Cedars Sinai Medical Center
When maintaining a live colony, hemizygous carriers may be bred with wildtype (noncarrier) mice from the colony or C57BL/6J inbred mice (Stock No. 000664). Hemizygous males on a C57BL/6J genetic background have an average survival time of approximately 3.5 months (97 +/- 11 days); this is earlier lethality than hemizygous males on a mixed C57BL/6;CBA genetic background. On a C57BL/6J genetic background, hemizygous females live significantly longer than hemizygous males. The intestinal dysmotility phenotype and sudden death observed in these mice can be mitigated by the use of jellified food.(Herdewyn et. al. Mol Neuro 9:24, 2014)The donating investigator has not attempted to make homozygous mice.
When using the Prp-TDP43A315T mouse strain in a publication, please cite the originating article(s) and include JAX stock #010700 in your Materials and Methods section.
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