The Jackson Laboratory will not distribute double transgenic mice. Instead, we will distribute the individual transgenic lines; that is, mice having either the NEFH-tTA transgene (see Stock No. 025397) or the tetO-hTDP-43-WT transgene (see Stock No. 016841).
Stock No. 028413 is a regulatable control double transgenic line that exhibits broad nuclear hTDP-43-WT expression in the brain and spinal cord, without the formation of cytoplasmic TDP-43 pathology. These mice are a control strain for the rNLS8 model (Stock No. 028412), and both are useful in studying amyotrophic lateral sclerosis (ALS) / frontotemporal lobar degeneration (FTLD).
Users should be aware that regulatable control double transgenic mice harboring both transgenic alleles will exhibit broad nuclear hTDP-43-WT expression in brain and spinal cord (although no cytoplasmic TDP-43 pathology is expected), and must be provided tetracycline or a suitable analog (such as doxycycline) for maintenance in a non-expressing condition.
Virginia M Lee, University of Pennsylvania
Genetic Background | Generation |
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|
Allele Type |
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Transgenic (Inducible, Inserted expressed sequence, Humanized sequence) |
Allele Type |
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Transgenic (Transactivator) |
The Jackson Laboratory will not distribute double transgenic mice. Instead, we will distribute the individual transgenic lines; that is, mice having either the NEFH-tTA transgene (see Stock No. 025397) or the tetO-hTDP-43-WT transgene (see Stock No. 016841).
These mice are useful in studying amyotrophic lateral sclerosis (ALS) / frontotemporal lobar degeneration (FTLD). The phenotype of these mice is expected to be as described in Walker et al. 2015 Acta Neuropathol 130:643; details below.
Stock No. 028413 is the regulatable control double transgenic line for the rNLS8 model (Stock No. 028412; described below). Stock No. 028413 is created by breeding NEFH-tTA line 8 (Stock No. 025397) with TRE-promoter-driven human TDP-43 wildtype transgenic mice (tetO-hTDP-43-WT line 12 ; Stock No. 016841). On a mixed C57BL/6J x C3HeJ F1 genetic background, mice hemizygous for NEFH-tTA and hemizygous for tetO-hTDP-43-WT exhibit broad nuclear hTDP-43-WT expression in the brain and spinal cord, without the formation of cytoplasmic TDP-43 pathology.
Stock No. 028412 is the regulatable NLS (rNLS8) double transgenic line created by breeding NEFH-tTA line 8 (Stock No. 025397) with TRE-promoter-driven cytoplasmic-insoluble human TDP-43ΔNLS transgenic mice (tetO-hTDP-43-ΔNLS line 4 ; Stock No. 014650). On a mixed C57BL/6J x C3HeJ F1 genetic background, mice hemizygous for NEFH-tTA and hemizygous for tetO-hTDP-43-ΔNLS exhibit lethal characteristics of amyotrophic lateral sclerosis (ALS) / frontotemporal lobar degeneration (FTLD) when maintained in the absence of the tetracycline analog, doxycycline (dox). Specifically, they exhibit widespread, high levels of hTDP-43ΔNLS expression in neurons of both the brain and spinal cord (SC) as early as 1 week off-dox. The brain/SC combination of hTDP-43-ΔNLS expression accounts for the spinal motor neuron loss and muscle denervation; resulting in a rapid, robust and progressive neurodegenerative ALS-like phenotype (including motor deficits, denervation of neuromuscular junctions, motor neuron loss and premature death at ~8-20 weeks). Upon administration of dox, the observed TDP-43 pathology and functional deficits were found to be largely reversible, even after neurodegeneration was underway (~8 weeks of hTDP-43-ΔNLS expression).
Importantly, the donating investigator reports that the human NEFH promoter in NEFH-tTA line 8 drives slightly higher levels of tTA expression in the cortex compared to their experiences with the mouse Camk2a promoter used in Camk2a-tTA mice (greater than ~10-fold higher than endogenous NEFH versus ~8-fold higher than endogenous CAMK2A). In addition, the human NEFH promoter directs tTA expression in spinal cord (whereas the mouse Camk2a promoter did not).
Stock No. 028413 is the regulatable control double transgenic line created by breeding NEFH-tTA line 8 (Stock No. 025397) with TRE-promoter-driven human TDP-43 wildtype transgenic mice (tetO-hTDP-43-WT line 12 ; Stock No. 016841). Both transgenes were designed in the laboratory of Dr. Virginia Man-Yee Lee (University of Pennsylvania).
Expressed Gene | TARDBP, TAR DNA binding protein, human |
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Site of Expression | When bred to mice expressing tetracycline transactivator (tTA), tetracycline or its analog doxycycline (DOX) administration results in the expression of human TAR DNA binding protein (TARDBP) in transactivator expressing tissues of the offspring. |
Expressed Gene | tTA, tetracycline-controlled transactivator, E. coli |
Site of Expression | tTA is expressed in developmental late stage of the cortex, cerebellum and hippocampus, with expression also observed in olfactory bulb and in the rest of the brain. |
Allele Name | transgene insertion 12, Virginia M Y Lee |
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Allele Type | Transgenic (Inducible, Inserted expressed sequence, Humanized sequence) |
Allele Synonym(s) | hTDP-43-WT12 |
Gene Symbol and Name | Tg(tetO-TARDBP)12Vle, transgene insertion 12, Virginia M Y Lee |
Gene Synonym(s) | |
Promoter | tetO, tet operator, |
Expressed Gene | TARDBP, TAR DNA binding protein, human |
Site of Expression | When bred to mice expressing tetracycline transactivator (tTA), tetracycline or its analog doxycycline (DOX) administration results in the expression of human TAR DNA binding protein (TARDBP) in transactivator expressing tissues of the offspring. |
Strain of Origin | (C57BL/6J x C3H/HeJ)F1 |
Chromosome | UN |
Molecular Note | The tetracycline responsive promoter drives inducible expression of the wild-type human cDNA. Four lines were generated (4, 5, 8, and 12). |
Mutations Made By | Susan Leight, University of Pennsylvania |
Allele Name | transgene insertion 8, Virginia M-Y Lee |
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Allele Type | Transgenic (Transactivator) |
Allele Synonym(s) | NEFH-tTA |
Gene Symbol and Name | Tg(NEFH-tTA)8Vle, transgene insertion 8, Virginia M-Y Lee |
Gene Synonym(s) | |
Promoter | NEFH, neurofilament heavy, human |
Expressed Gene | tTA, tetracycline-controlled transactivator, E. coli |
Site of Expression | tTA is expressed in developmental late stage of the cortex, cerebellum and hippocampus, with expression also observed in olfactory bulb and in the rest of the brain. |
Strain of Origin | (C57BL/6J x C3H/HeJ)F1 |
Chromosome | UN |
Molecular Note | The construct consists of ~18 kbp of the human neurofilament heavy polypeptide promoter (NEFH; from BAC RP11-91J21) upstream of the tetracycline-regulated transactivator gene (tTA or "Tet-Off"), followed by a polyA signal. Founder line 8 has its highest tTA expression in developmental late stage of the cortex, cerebellum and hippocampus, with expression also observed in olfactory bulb and in the rest of the brain. |
When using the NEFH-hTDP-43-WT mouse strain in a publication, please cite the originating article(s) and include JAX stock #028413 in your Materials and Methods section.
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The Jackson Laboratory has rigorous genetic quality control and mutant gene genotyping programs to ensure the genetic background of JAX® Mice strains as well as the genotypes of strains with identified molecular mutations. JAX® Mice strains are only made available to researchers after meeting our standards. However, the phenotype of each strain may not be fully characterized and/or captured in the strain data sheets. Therefore, we cannot guarantee a strain's phenotype will meet all expectations. To ensure that JAX® Mice will meet the needs of individual research projects or when requesting a strain that is new to your research, we suggest ordering and performing tests on a small number of mice to determine suitability for your particular project. We do not guarantee breeding performance and therefore suggest that investigators order more than one breeding pair to avoid delays in their research.
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