In the Hip1LSP-H/P strain, a floxed-STOP cassette causes termination of the endogenous huntingtin interacting protein 1 (Hip1) gene and a human HIP1/PDGFbR (H/P) cDNA fused to another polyA site and a neomycin resistance (neo) cassette, replace endogenous exons 2-7.
Theodora S Ross, University of Texas Southwestern Medical Center
In the Hip1LSP-H/P strain, a floxed-STOP cassette causes termination of the endogenous huntingtin interacting protein 1 (Hip1) gene and a human HIP1/PDGFbR (H/P) cDNA fused to another polyA site and a neomycin resistance (neo) cassette, replace endogenous exons 2-7. Heterozygous mice are viable, fertile, and normal in size. These mice exhibit gross micro-ophthalmia and cataracts. When bred to mice that express Cre recombinase, offspring will have the floxed-STOP cassette deleted in the cre-expressing tissue(s), resulting in H/R fusion protein overexpression in cre-expressing cells. The overexpression of H/P mimics the human chromosomal translocation, t(5;7)(q33;q11.2), leading to constitutively active PDGFbR signalling and chronic myelomonocytic leukemia (CMML) development in humans. For example, H/P is able to transform hematopoietic cells to factor-independent growth in culture. When Hip1LSP-H/P mice are bred to mice that express Cre recombinase driven by the myxovirus resistance 1 Mx1 promoter (see Stock No. 003556), these mice do not exhibit widespread neoplasia, although some had enlarged spleens, after one year of age, with signs of mild myeloproliferative disorder (MPD). When these Mx1-Cre;Hip1+/LSL-H/P mice are bred to mice carrying a similar type of knockin allele of the human chromosomal translocation t(8;21)(q22;q22) mutation Aml1/Eto (A/E), all of the resulting double knockin mice (H/P;A/E) develop aggressive MPD after interferon activation. Treatment with imatinib, a tyrosine kinase inhibitor, restored the mutant phenotypes to that of wildtype mice, but did not prevent disease transfer upon bone marrow transplantation into syngeneic lethally irradiated mice. These Hip1LSP-H/P mice may be useful for analysis of cooperating conditional mutations in hematopoietic malignancy development, and PDGFbR activation in the initiation and maintenance of CMML and other types of MPDs.
For example, when crossed to a strain expressing interferon-inducible Cre recombinase in most tissues (see Stock No. 003556), this mutant mouse strain may be useful in studies of myeloproliferative disorders.
A targeting vector was designed to insert a loxP-flanked SV40 polyadenylation (polyA) site upstream of exon 2 of the huntingtin interacting protein 1 (Hip1) gene. A human HIP1 cDNA fused to human platelet derived growth factor beta receptor (PGDFβR) cDNA (H/P), followed by another polyA site and a neomycin resistance (neo) cassette, replace endogenous exons 2-7 of Hip1. The construct was electroporated into 129X1/SvJ-derived RW4 embryonic stem (ES) cells. Correctly targeted ES cells were injected into blastocysts and the resulting chimeric mice were bred to C57BL/6 to generate a colony of Hip1LSP-H/P mice. The donating investigator reported that these mice were backcrossed for at least 7 generations to C57BL/6 (see Smp note below). Upon arrival at The Jackson Laboratory, mice were bred to C57BL/6J (Stock No. 000664) for at least one generation to establish the colony.
A 32 SNP (single nucleotide polymorphism) panel analysis, with 27 markers covering all 19 chromosomes and the X chromosome, as well as 5 markers that distinguish between the C57BL/6J and C57BL/6N substrains, was performed on the rederived living colony at The Jackson Laboratory Repository. Twenty-four markers throughout the genome suggested a C57BL/6 genetic background, while two were found to be segregating for 129 and one was segregating for an unknown strain. 3 of 5 markers that determine C57BL/6J from C57BL/6N were found to be segregating. These data suggest the mice sent to The Jackson Laboratory Repository were on a mixed C57BL/6J ; C57BL/6N genetic background.
|Allele Name||targeted mutation 4, Theodora S Ross|
|Allele Type||Targeted (Conditional ready (e.g. floxed), Humanized sequence, No functional change)|
|Gene Symbol and Name||Hip1, huntingtin interacting protein 1|
|Strain of Origin||129X1/SvJ|
|Molecular Note||A floxed STOP cassette was inserted upstream of exon 2. Exons 3 through 7 were replaced with a fusion of human HIP1 and PDGFRB, to model human t(5;7) translocation, and a neo cassette. Removal of the STOP cassette is required for expression of the fusion gene.|
|Mutations Made By|| |
Theodora Ross, University of Texas Southwestern Medical Center
When maintaining a live colony, heterozygous mice may be bred to wildtype mice from the colony or to C57BL/6J inbred mice (Stock No. 000664).
When using the B6.129X1-Hip1tm4Tsr/J mouse strain in a publication, please cite the originating article(s) and include JAX stock #013547 in your Materials and Methods section.
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