Pxr-Car Knockout Mouse

Constitutive Knock Out

Pxr-Car Constitutive Knock Out Mouse Model

  • Model #
  • Genotype
  • Nomenclature
  • 8222-F
    ko/ko;ko/ko
    C57BL/6-Nr1i2tm3Arte Nr1i3tm1.1Arte
  • 8222-M
    ko/ko;ko/ko
    C57BL/6-Nr1i2tm3Arte Nr1i3tm1.1Arte
  • This targeted mutation strain carries a deletion of the mouse Nr1i2 and Nr1i3 genes which encode for the nuclear receptors PXR and CAR.
  • Useful in defining the effect of PXR and CAR on CYP induction and therefore pharmacokinetics, drug toxicity, and efficacy.
  • In conjunction with the Humanized PXR-CAR Mouse line (Taconic Model 8223), this model has relevance for the prediction of the hazard of non-genotoxic rodent liver growth carcinogens to humans.

Genetic Background:

C57BL/6 Background

Origin:

The Pxr-Car Knockout mouse was developed by Taconic in collaboration with CXR Biosciences. The double knockout model was generated by crossing each humanized single gene mouse line with a PhiC31 deleter mouse. The two single knockout lines were then crossed together. The Humanized PXR Mouse model was created through a knock in of a human PXR cDNA/genomic construct onto the ATG of murine PXR in C57BL/6NTac-derived ES cells. The Humanized CAR Mouse model was created through a knock in of a human CAR construct containing the genomic sequence from the translational start site on exon 2 to exon 9 onto the ATG of murine CAR in C57BL/6NTac-derived ES cells. In both cases targeted ES cells were injected into BALB/cJBomTac blastocysts and the resultant chimeras were backcrossed to a Flpe deleter strain on C57BL/6J to eliminate selection markers. The Pxr Knockout Mouse model was derived from the Humanized PXR Mouse line through a PhiC31-mediated deletion of the human PXR sequence. Mouse exon 2, carrying the translational start site, is deleted in the knockout, while mouse exon 1 and exons 3-9 are still present. A splice acceptor polyA motif included in the targeting vector causes splicing of exon 1 to a polyA motif and thereby terminates the transcription. The absence of PXR protein was proven experimentally. The Car Knockout Mouse model was derived from the Humanized CAR Mouse line through a PhiC31-mediated deletion of the human CAR sequence. This deletes all exons coding for functional domains of CAR (exon 3-9). The absence of CAR protein was proven experimentally. The Pxr-Car Knockout Mouse line was obtained by crossing the single knockout mouse lines for both receptors. Taconic received stock in 2008, and the line was embryo transfer derived. The colony is maintained by mating double homozygotes.


Color:

Black

Species:

Mouse

Initial Publication:

Scheer N, Ross J, Rode A, Zevnik B, Niehaves S, Faust N, Wolf CR. (2008) A novel panel of mouse models to evaluate the role of human pregnane X receptor and constitutive androstane receptor in drug response. J. Clin. Invest. 118(9): 3228-3239.

Additional Publication:
Ross J, Plummer SM, Rode A, Scheer N, Bower CC, Vogel O, Henderson CJ, Wolf CR, Elcombe CR. (2010). Human constitutive androstane receptor (CAR) and pregnane X receptor (PXR) support the hypertrophic but not the hyperplastic response to the murine non-genotoxic hepatocarcinogens phenobarbital and chlordane in vivo. Toxicol Sci 116(2):452-66.



Conditions of Use - Model 8222

This Model is produced and distributed under rights to patents and intellectual property owned by Taconic or licensed from various institutions. Taconic sells this model to purchaser, and grants to each purchaser a right under Taconic's own or sublicensable rights in such licensed patents and intellectual property to use the purchased Model in consideration of purchasers' acknowledgement of and agreement to the Terms and Conditions of Sale and the following terms of use:

  • Title to this Model and biological materials derived from it remains with Taconic Biosciences, Inc.
  • The Model will be used for research purposes only.
  • The Model will not be bred except to obtain embryos or fetuses required for research purposes.
  • The Model and biological materials derived from it will not be distributed to third parties or used for commercial purposes
  • Nonprofit purchasers may not use this Model and/or biological materials derived from it in sponsored research or contract research studies unless it is purchased at the for-profit price.