Prp-TDP-43Q331K-low 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 moderate huTDP-43*Q331K overexpressing founder line (Prp-TDP-43Q331K [~1.5x] mice; Stock No. 017933), these Prp-TDP-43Q331K-low transgenic mice may be useful in studying motor dysfunction in the neurodegenerative disorder amyotrophic lateral sclerosis (ALS; Lou Gehrig's Disease).
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 109 (Prp-TDP-43Q331K-low).
The Prp-TDP-43Q331K-low mice have approximately the same total TDP-43 mRNA/protein expression levels compared to endogenous TDP-43 in non-transgenic mice (huTDP-43*Q331K levels are slightly less than endogenous TDP-43 in non-transgenic mice). By ten months of age, Prp-TDP-43Q331K-low 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. Unlike the founder line with moderate huTDP-43*Q331K overexpression levels (Prp-TDP-43Q331K [~1.5x] line 103; Stock No. 017933), these Prp-TDP-43Q331K-low mice 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 109 was identified with approximately the same total TDP-43 (slightly less huTDP-43*Q331K) expression levels in spinal cord as compared to endogenous TDP-43 in non-transgenic mice. These Prp-TDP-43Q331K-low transgenic mice were bred with C57BL/6NCrl females for at least eight additional 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 109, Don W Cleveland|
|Allele Type||Transgenic (Humanized sequence, Inserted expressed sequence)|
|Gene Symbol and Name||Tg(Prnp-TARDBP*Q331K)109Dwc, transgene insertion 109, 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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