Prp-TDP-43Q331K [~1.5x] transgenic mice have expression of a myc-tagged, human TAR DNA binding protein carrying the ALS-linked Q331K mutation (huTDP-43*Q331K) directed to brain and spinal cord by the mouse prion protein promoter. Along with the lower huTDP-43*Q331K expressing founder line (Prp-TDP-43Q331K-low; Stock No. 017930), these Prp-TDP-43Q331K [~1.5x] transgenic mice may be useful in studying motor dysfunction in the neurodegenerative disorder amyotrophic lateral sclerosis (ALS; Lou Gehrig's Disease), specifically motor dysfunction and L5 motor axon/lower motor neuron degeneration.
Dr. Don Cleveland, Ludwig Institute for Cancer Res. (UCSD)
Prp-TDP-43Q331K transgenic mice express a myc-tagged, human TAR DNA binding protein cDNA sequence modified to have the ALS-linked Q331K mutation (huTDP-43*Q331K), all under the direction of the mouse prion protein promoter (PrP). As expected for the PrP promoter, transgene expression is confined primarily to central nervous system (brain and spinal cord), with very low to no expression in other tested tissues (testis not examined). Anti-myc antibody staining shows huTDP-43*Q331K accumulation in the nuclei of neurons as well as glial cells of the spinal cord and brain, with a corresponding downregulation of endogenous mouse TDP-43. The transgene is flanked by loxP sites, allowing it to be removed by introduction of Cre recombinase if desired. The phenotype below describes Prp-TDP-43Q331K transgenic mice from founder line 103 (Prp-TDP-43Q331K [~1.5x]).
The Prp-TDP-43Q331K [~1.5x] mice have moderate overexpression levels in total TDP-43 mRNA/protein, with an ~2.5-fold increase in total TDP-43 expression (huTDP-43*Q331K levels ~1.5-fold greater) compared to endogenous TDP-43 in non-transgenic mice. By three months of age, Prp-TDP-43Q331K [~1.5x] mice develop adult-onset motor dysfunction (as measured by rotarod performance) accompanied by a loss of hindlimb-grip strength and the appearance of muscle fasciculations. Pathologically, Prp-TDP-43Q331K [~1.5x] mice demonstrate ~30% loss of L5 motor axons and 30-45% loss of lower motor neurons by ten months of age (earlier timepoints not yet tested; May 2012). Of note, this latter phenotype is in contrast to Dr. Robert Baloh's Prp-TDP43A315T transgenic mice that primarily display a loss of upper motor neurons (Stock No. 010700). Also note, this is in contrast to the founder line with low huTDP-43*Q331K overexpression (Prp-TDP-43Q331K-low line 109; Stock No. 017930), that do not exhibit loss of motor axons or neurons.
A full-length human TAR DNA binding protein (TARDBP or TDP-43) cDNA sequence was modified to have both an N-terminal myc tag and the glutamine to lysine substitution at amino acid 331 associated with familial ALS (huTDP-43*Q331K). This huTDP-43*Q331K cDNA sequence was inserted between exon 2 and exon 3 of mouse prion protein (PrP or Prnp) gene at two unique XhoI sites in the MoPrP.XhoI plasmid vector (ATCC#JHU-2). The resulting MoPrP.XhoI-mychuTDP-43*Q331K transgene was flanked with loxP sites, and then injected into the pronuclei of fertilized C57BL6/C3H hybrid eggs, which were implanted into pseudopregnant female mice. Transgenic founder mice were bred to C57BL/6 mice, and founder line 103 was identified with ~2.5-fold greater total TDP-43 (~1.5-fold greater huTDP-43*Q331K) expression levels in spinal cord as compared to endogenous TDP-43 in non-transgenic mice. These Prp-TDP-43Q331K [~1.5x] transgenic mice were bred with C57BL/6NCrl females for at least nine generations prior to sending to The Jackson Laboratory Repository. Upon arrival, transgenic mice were bred to C57BL/6NJ inbred mice (Stock No. 005304) for at least one generations to establish The Jackson Laboratory Repository colony.
|Expressed Gene||TARDBP, TAR DNA binding protein, human|
|Site of Expression|
|Allele Name||transgene insertion 103, Don W Cleveland|
|Allele Type||Transgenic (Humanized sequence, Inserted expressed sequence)|
|Gene Symbol and Name||Tg(Prnp-TARDBP*Q331K)103Dwc, transgene insertion 103, Don W Cleveland|
|Promoter||Prnp, prion protein, mouse, laboratory|
|Expressed Gene||TARDBP, TAR DNA binding protein, human|
|Strain of Origin||C57BL/6 x C3H|
When maintaining a live colony, hemizygous mice may be bred with wildtype (noncarrier) mice from the colony or with C57BL/6NJ inbred mice (Stock No. 005304). The donating investigator has not attempted to generate homozygous mice to date (May 2012).
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