Description

The genotypes of the animals provided may not reflect those discussed in the strain description or the mating scheme utilized by The Jackson Laboratory prior to cryopreservation. Please inquire for possible genotypes for this specific strain.

Strain Information

Type Congenic; Mutant Strain; Targeted Mutation; Additional information on Genetically Engineered and Mutant Mice. Visit our online Nomenclature tutorial. Additional information on Congenic nomenclature. Species laboratory mouse Generation N7pN1 Generation Definitions   Donating Investigator Theodora Ross,   University of Michigan

Description
In the Hip1^LSP-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 Hip1^LSP-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 Hip1^LSP-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.

Development
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 Hip1^LSP-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.

Control Information

	Control
	Wild-type from the colony
	000664 C57BL/6J	(approximate)
Considerations for Choosing Controls

Phenotype

Phenotype Information

View Related Disease (OMIM) Terms

Related Disease (OMIM) Terms provided by MGI

- Potential model based on gene homology relationships. Phenotypic similarity to the human disease has not been tested. Prostate Cancer   (HIP1)

View Mammalian Phenotype Terms

Mammalian Phenotype Terms provided by MGI

      assigned by genotype

The following phenotype information may relate to a genetic background differing from this JAX^® Mice strain.

Hip1^tm4Tsr/Hip1⁺

        involves: 129X1/SvJ * C57BL/6

• vision/eye phenotype
• cataracts   (MGI Ref ID J:151974)
• microphthalmia   (MGI Ref ID J:151974)

The following phenotype relates to a compound genotype created using this strain.
Contact JAX^® Services jaxservices@jax.org for customized breeding options.

Hip1^tm4Tsr/Hip1⁺ Tg(Mx1-cre)1Cgn/0

        involves: 129X1/SvJ * C57BL/6 * CBA   (conditional)

• mortality/aging
• increased sensitivity to xenobiotic induced morbidity/mortality
  • 71% of mice treated with pIpC, G-CSF, and ENU exhibit thymic tumors, splenomegaly, and/or death 10 months after treatment   (MGI Ref ID J:151974)
• hematopoietic system phenotype
• *normal* hematopoietic system phenotype
  • mice exhibit normal peripheral blood cell counts up to 1.5 years following induction with pIpC at 6 weeks   (MGI Ref ID J:151974)
• • abnormal myelopoiesis
    • at 1.5 years of age, 29% of enlarged spleens from mice induced with pIpC at 6 weeks exhibit myeloproliferative disorder compared to 7% of wild-type enlarged spleens   (MGI Ref ID J:151974)
  • abnormal spleen morphology
    • at 3 months, spleen structure in mice induced with pIpC at 6 weeks is moderately effaced unlike in wild-type mice   (MGI Ref ID J:151974)
  • • enlarged spleen
      • at 3 months, one mouse induced with pIpC at 6 weeks exhibited an enlarged spleen   (MGI Ref ID J:151974)
      • at 1.5 years of age, 47% of mice induced with pIpC at 6 weeks exhibit enlarged spleen compared to 20% in Tg(Mx1-cre)1Cgn mice   (MGI Ref ID J:151974)
      • 71% of mice treated with pIpC, G-CSF, and ENU exhibit thymic tumors, splenomegaly, and/or death 10 months after treatment   (MGI Ref ID J:151974)
    • increased spleen red pulp amount
      • at 1.5 years of age in mice induced with pIpC at 6 weeks   (MGI Ref ID J:151974)
  • decreased hematopoietic stem cell number
    • after 4 weeks of pIpC induction, the frequency of hematopoietic stem cells in the bone marrow is decreased compared to in wild-type mice   (MGI Ref ID J:151974)
    • however, at 1.5 years of age pIpC-induced mice exhibit a normal of hematopoeitic stem cells   (MGI Ref ID J:151974)
• tumorigenesis
• abnormal tumor incidence
  • mice treated with pIpC, G-CSF, and ENU exhibit myeloid and lymphoid neoplasias   (MGI Ref ID J:151974)
• • T cell derived lymphoma
    • 71% of mice treated with pIpC, G-CSF, and ENU exhibit thymic tumors, splenomegaly, and/or death 10 months after treatment   (MGI Ref ID J:151974)
  • increased liver tumor incidence
    • in one mouse induced with pIpC at 6 weeks   (MGI Ref ID J:151974)
  • • hepatocellular carcinoma
      • in one 9 month old in mouse induced with pIpC at 6 weeks   (MGI Ref ID J:151974)
• immune system phenotype
• abnormal myelopoiesis
  • at 1.5 years of age, 29% of enlarged spleens from mice induced with pIpC at 6 weeks exhibit myeloproliferative disorder compared to 7% of wild-type enlarged spleens   (MGI Ref ID J:151974)
• abnormal spleen morphology
  • at 3 months, spleen structure in mice induced with pIpC at 6 weeks is moderately effaced unlike in wild-type mice   (MGI Ref ID J:151974)
• • enlarged spleen
    • at 3 months, one mouse induced with pIpC at 6 weeks exhibited an enlarged spleen   (MGI Ref ID J:151974)
    • at 1.5 years of age, 47% of mice induced with pIpC at 6 weeks exhibit enlarged spleen compared to 20% in Tg(Mx1-cre)1Cgn mice   (MGI Ref ID J:151974)
    • 71% of mice treated with pIpC, G-CSF, and ENU exhibit thymic tumors, splenomegaly, and/or death 10 months after treatment   (MGI Ref ID J:151974)
  • increased spleen red pulp amount
    • at 1.5 years of age in mice induced with pIpC at 6 weeks   (MGI Ref ID J:151974)
• homeostasis/metabolism phenotype
• increased sensitivity to xenobiotic induced morbidity/mortality
  • 71% of mice treated with pIpC, G-CSF, and ENU exhibit thymic tumors, splenomegaly, and/or death 10 months after treatment   (MGI Ref ID J:151974)

View Research Applications

Research Applications

This mouse can be used to support research in many areas including:

Cancer Research
Chronic Myelogenous Leukemia
Genes Regulating Growth and Proliferation

Cell Biology Research
Genes Regulating Growth and Proliferation

Developmental Biology Research
Perinatal Lethality
      Homozygous

Hematological Research
Hematopoietic Defects
Neutrophil Defects

Internal/Organ Research
Liver Defects
Lung Defects
Spleen Defects

Genes & Alleles

Gene & Allele Information provided by MGI

Allele Symbol		Hip1tm4Tsr
Allele Name		targeted mutation 4, Theodora S Ross
Allele Type		Targeted (Floxed/Frt)
Common Name(s)		Hip1LSL-H/P;
Mutation Made By		Theodora Ross,   University of Michigan
Strain of Origin		129X1/SvJ
Gene Symbol and Name		Hip1, huntingtin interacting protein 1
Chromosome		5
Gene Common Name(s)		2610109B09Rik; A930014B11Rik; E130315I21Rik; HIP-1; ILWEQ; MGC:27616; RIKEN cDNA 2610109B09 gene; RIKEN cDNA A930014B11 gene; RIKEN cDNA E130315I21 gene;
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. [MGI Ref ID J:151974]

Genotyping

Genotyping Information

Genotyping Protocols

Hip1^tm4Tsr, Separated PCR

Helpful Links

Genotyping resources and troubleshooting

References

References provided by MGI

Selected Reference(s)

Oravecz-Wilson KI; Philips ST; Yilmaz OH; Ames HM; Li L; Crawford BD; Gauvin AM; Lucas PC; Sitwala K; Downing JR; Morrison SJ; Ross TS. 2009. Persistence of leukemia-initiating cells in a conditional knockin model of an imatinib-responsive myeloproliferative disorder. Cancer Cell 16(2):137-48. [PubMed: 19647224]  [MGI Ref ID J:151974]

Health & husbandry

The genotypes of the animals provided may not reflect those discussed in the strain description or the mating scheme utilized by The Jackson Laboratory prior to cryopreservation. Please inquire for possible genotypes for this specific strain.

Health & Colony Maintenance Information

Animal Health Reports

Production of mice from cryopreserved embryos or sperm occurs in a maximum barrier room, G200.

Colony Maintenance

Breeding & Husbandry	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).

Pricing and Purchasing

Pricing, Supply Level & Notes, Controls

Control Information

	Control
	Wild-type from the colony
	000664 C57BL/6J	(approximate)
Considerations for Choosing Controls
Control Pricing Information for Genetically Engineered Mutant Strains.

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The Jackson Laboratory's Genotype Promise

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.

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Terms of Use

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