Description

Strain Information

Type Congenic; Mutant Stock; Targeted Mutation; Additional information on Genetically Engineered Mutant Mice. Mating System Heterozygote x +/+ sibling         (Female x Male) Species laboratory mouse Generation N11+ (30-SEP-08)   Donating Investigator Raymond Burk,   Vanderbilt University

Description
Mice that are homozygous for this targeted mutation are slightly smaller in size than wildtype littermates and exhibit poor grooming and hypoactivity. As early as 20 weeks of age, homozygotes develop anemia with diminished serum iron and increased serum ferritin. Histological analysis reveals iron accumulation in kidney and liver. Elevated oxidized proteins and lipid peroxidation develop in the liver and kidney. Homozygotes develop progressive chronic inflammatory disease, including enlarged spleen and lymph nodes, inflammatory infiltrates, glomerulonephritis, fibrosis. Homozygous male mice have smaller testis than wildtype controls. Homozygotes occur at a lower than expected frequency, or are not produced, from heterozygous crosses and have decreased postnatal survival. An almost undetectable abnormal gene product (mRNA) is detected by Northern blot analysis of total splenic RNA. This mutant mouse strain may be useful in studies of hemochromatosis, inflammation and iron metabolism.

In an attempt to offer alleles on well-characterized or multiple genetic backgrounds, alleles are frequently moved to a genetic background different from that on which an allele was first characterized. This is the case for the strain above. It should be noted that the phenotype could vary from that originally described. We will modify the strain description if necessary as published results become available.

Development
A targeting vector containing PGK-neo cassette was used to disrupt 3.7kb of sequence containing exons 3, 4 and part of exon 5. The construct was electroporated into 129S2/SvPas-derived D3 embryonic stem (ES) cells. Correctly targeted ES cells were injected into C57BL/6 blastocysts. The resulting chimeric animals were crossed to C57BL/6 mice, and then backcrossed to FVB for 10 generations.

Control Information

	Control
	Wild-type from the colony
	001800 FVB/NJ
Considerations for Choosing Controls

Additional Web Information

Congenic Nomenclature

Phenotype

Phenotype Information

View Related Disease (OMIM) Terms

Related Disease (OMIM) Terms

Hemochromatosis; HFE - Models with phenotypic similarity to human disease where etiologies are distinct.2

2 Human genes are associated with this disease. Orthologs of those genes do not appear in the mouse genotype(s).

View Mammalian Phenotype Terms

Mammalian Phenotype Terms

      assigned by genotype

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

Hmox1^tm1Poss/Hmox1^tm1Poss

        involves: 129S2/SvPas * C57BL/6

• lethality-postnatal
• postnatal lethality (MGI Ref ID J:79254)
  • homozygotes exhibit low postnatal survival, with only 20% of the expected number of homozygotes obtained at 3 weeks; a similar survival % is observed in matings between homozygous and heterozygous mutant mice
  • percentage of surviving homozygotes can be increased to 48% of those expected by in vitro fertilization techniques using gametes from homozygous and heterozygous animals
• life span-post-weaning/aging
• premature death (MGI Ref ID J:79254)
  • post-weaning survivors commonly die after 25 weeks of age; one homozygote lived up to 22 months
• hematopoietic system phenotype
• abnormal leukocyte cell number (MGI Ref ID J:79254)
  • adult homozygotes exhibit high peripheral white blood cell counts
• abnormal spleen cellularity (MGI Ref ID J:79254)
  • adult homozygotes display high splenic CD4⁺:CD8⁺ T-cell ratios with numerous activated CD4⁺ T cells
• spleen hyperplasia (MGI Ref ID J:79254)
  • adult homozygotes display spleen follicular hyperplasia
• anisocytosis (MGI Ref ID J:79254)
  • by 20 weeks of age, homozygotes exhibit variable erythrocyte size on blood smears
• decreased erythrocyte cell number (MGI Ref ID J:79254)
  • at 10 (but not at 6) weeks of age, homozygotes start displaying significantly lower red blood cell counts relative to wild-type mice
• decreased hematocrit (MGI Ref ID J:79254)
  • at 10 weeks of age, homozygotes start displaying significantly reduced hematocrits relative to wild-type mice
• decreased hemoglobin content (MGI Ref ID J:79254)
  • at 10 (but not at 6) weeks of age, homozygotes start displaying significantly reduced blood hemoglobin concentrations relative to wild-type mice
• decreased mean corpuscular volume (MGI Ref ID J:79254)
  • at 10 weeks of age, homozygotes start displaying extremely reduced mean corpuscular volumes relative to wild-type mice
• enlarged spleen (MGI Ref ID J:79254)
  • adult homozygotes exhibit enlarged spleens due to both extramedullary hematopoiesis and follicular hyperplasia
• spleen hyperplasia (MGI Ref ID J:79254)
  • adult homozygotes display spleen follicular hyperplasia
• extramedullary hematopoiesis (MGI Ref ID J:79254)
  • adult homozygotes exhibit extramedullary hematopoiesis
• microcytic anemia (MGI Ref ID J:79254)
  • at 20-24 weeks of age, homozygotes display normochromic and microcytic anemia which becomes severe by 40-55 weeks of age
• homeostasis/metabolism phenotype
• abnormal iron homeostasis (MGI Ref ID J:79254)
  • by 20 weeks of age, homozygotes exhibit an increased total iron-binding capacity (high serum transferrin levels), resulting in a reduced iron saturation percentage and increased iron deposition relative to wild-type mice
  • by ~50 weeks of age, all homozygotes exhibit pathological iron-loading (nonheme iron deposits) in renal proximal cortical tubules, liver Kupffer cells, hepatocytes, and hepatic vascular tissue (with variable severity) while the spleen remains unaffected
• hypoferremia (MGI Ref ID J:79254)
  • by 20 weeks of age, homozygotes display significantly reduced serum iron levels relative to wild-type mice
  • despite iron deficiency, homozygotes exhibit progressively increasing serum ferritin levels up to ~50 weeks of age
• increased blood urea nitrogen level (MGI Ref ID J:62437)
  • at day 3 after cisplatin administration, homozygotes exhibit significantly increased BUN values, indicating exacerbated renal dysfunction relative to similarly treated wild-type mice; no significant differences in body weight reduction are observed
• immune system phenotype
• abnormal leukocyte cell number (MGI Ref ID J:79254)
  • adult homozygotes exhibit high peripheral white blood cell counts
• abnormal lymph node cellularity (MGI Ref ID J:79254)
  • adult homozygotes display high lymph node CD4⁺:CD8⁺ T-cell ratios with numerous activated CD4⁺ T cells
• abnormal spleen cellularity (MGI Ref ID J:79254)
  • adult homozygotes display high splenic CD4⁺:CD8⁺ T-cell ratios with numerous activated CD4⁺ T cells
• spleen hyperplasia (MGI Ref ID J:79254)
  • adult homozygotes display spleen follicular hyperplasia
• chronic inflammation (MGI Ref ID J:79254)
  • homozygotes develop a progressive chronic inflammatory disease
• enlarged lymph nodes (MGI Ref ID J:79254)
• enlarged spleen (MGI Ref ID J:79254)
  • adult homozygotes exhibit enlarged spleens due to both extramedullary hematopoiesis and follicular hyperplasia
• spleen hyperplasia (MGI Ref ID J:79254)
  • adult homozygotes display spleen follicular hyperplasia
• glomerulonephritis (MGI Ref ID J:79254)
  • at ~50 weeks, homozygotes display glomerulonephritis, caused either by iron toxicity or by deposition of immune complexes
• liver inflammation (MGI Ref ID J:79254)
  • at ~50 weeks of age, homozygotes show hepatic inflammatory cell infiltrates, consisting of lymphocytes, plasma cells, neutrophils, and macrophages
  • many infiltrates are periportal while others show a predilection for the portal venous tissue which often contains iron deposits
  • hepatic vascular lesions invlove the proliferation of smooth muscle, the infiltration of neutrophils and lymphocytes into the vessel wall, and adherence of monocytes to the inner vessel wall
• lung inflammation (MGI Ref ID J:79254)
  • at ~50 weeks of age, homozygotes occasionally exhibit vascular and perivascular infiltrates in their lungs
• renal/urinary system phenotype
• glomerulonephritis (MGI Ref ID J:79254)
  • at ~50 weeks, homozygotes display glomerulonephritis, caused either by iron toxicity or by deposition of immune complexes
• glomerulosclerosis (MGI Ref ID J:79254)
  • by ~75 weeks, homozygotes display severely damaged glomeruli with membranous proliferation, lobularity, crescent formation, and sclerosis
• increased renal tubule apoptosis (MGI Ref ID J:62437)
  • at day 3 after cisplatin administration, homozygotes display a 6.6-fold increase in renal tubular apoptosis whereas wild-type mice show a 3-fold increase over saline-treated mice, respectively
• kidney failure (MGI Ref ID J:62437)
  • at day 3 after cisplatin-induced renal injury, homozygotes develop more severe renal failure than wild-type mice
• renal tubular necrosis (MGI Ref ID J:62437)
  • at day 3, cisplatin-treated homozygotes exhibit severe changes in acute renal injury, including tubular necrosis, degeneration, loss of brush border, red cell extravasation, tubular casts, and apoptotic bodies in the proximal and distal tubules; in contrast, wild-type mice display only mild changes with loss of brush border and red cell extravasation
• liver/biliary system phenotype
• liver fibrosis (MGI Ref ID J:79254)
  • at ~50 weeks of age, homozygotes display fibrosis within hepatic inflammatory cell infiltrates
  • regenerative nodules indicative of hepatic injury are occasionally observed
• liver inflammation (MGI Ref ID J:79254)
  • at ~50 weeks of age, homozygotes show hepatic inflammatory cell infiltrates, consisting of lymphocytes, plasma cells, neutrophils, and macrophages
  • many infiltrates are periportal while others show a predilection for the portal venous tissue which often contains iron deposits
  • hepatic vascular lesions invlove the proliferation of smooth muscle, the infiltration of neutrophils and lymphocytes into the vessel wall, and adherence of monocytes to the inner vessel wall
• behavior/neurological phenotype
• hypoactivity (MGI Ref ID J:79254)
  • as early as 25 weeks of age, most post-weaning survivors appear less active than wild-type mice
• poor grooming (MGI Ref ID J:79254)
  • as early as 25 weeks of age, most post-weaning survivors exhibit poor grooming
• growth/size phenotype
• decreased body size (MGI Ref ID J:79254)
  • homozygotes are slightly smaller than wild-type or heterozygous littermates from birth to early adulthood
• cachexia (MGI Ref ID J:79254)
  • between 20 and 40 weeks of age, most surviving homozygotes exhibit significant weight loss indicative of wasting
• cellular phenotype
• oxidative stress (MGI Ref ID J:79254)
  • as a result of iron deposition, livers from 20-24-wk-old homozygotes display increased oxidized proteins and lipid peroxidation values of 51% and 95% while kidneys show increases of 69% and 74% relative to heterozygous values, respectively
  • notably, mutant brains, which have no iron deposition, show no evidence of enhanced oxidative damage
• reproductive system phenotype
• infertility (MGI Ref ID J:79254)
  • as early as 25 weeks of age, most post-weaning survivors breed poorly
  • mating pairs of homozygous mutant mice fail to yield viable litters
• small testis (MGI Ref ID J:79254)
  • mature male homozygotes show a ~25% reduction in testicular size relative to similarly sized heterozygotes
• endocrine/exocrine gland phenotype
• small testis (MGI Ref ID J:79254)
  • mature male homozygotes show a ~25% reduction in testicular size relative to similarly sized heterozygotes
• respiratory system phenotype
• lung inflammation (MGI Ref ID J:79254)
  • at ~50 weeks of age, homozygotes occasionally exhibit vascular and perivascular infiltrates in their lungs

View Research Applications

Research Applications

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

Hematological Research
Anemia, Iron Deficiency and Transport Defects (hemochromatosis)

Immunology and Inflammation Research
Inflammation

Internal/Organ Research
Liver Defects (hemochromatosis)

Metabolism Research
Hemochromatosis (iron metabolism defects)

Genes & Alleles

Gene & Allele Information

Allele Symbol		Hmox1tm1Poss
Allele Name		targeted mutation 1, Kenneth D Poss
Allele Type		Targeted (knock-out)
Common Name(s)		HO-1-; Hmox1-;
Mutation Made By		Kenneth Poss,   Massachusetts Institute of Technology
Strain of Origin		129S2/SvPas
ES Cell Line Name		D3
ES Cell Line Strain		129S2/SvPas
Gene Symbol and Name		Hmox1, heme oxygenase (decycling) 1
Chromosome		8
Gene Common Name(s)		D8Wsu38e; DNA segment, Chr 8, Wayne State University 38, expressed; HEOXG; HO-1; HO1; HSP32; Heox; Hmox; bK286B10; heme oxygenase 1; hemoxygenase;
Molecular Note		A 3.7 kb fragment encompassing exons 3, 4, and a portion of 5 was replaced with a neomycin selection cassette. The deleted region consisted of approximately 85% of the coding region (226 residues). A low level of aberrantly spliced transcript was identified in homozygous mutant mice by Northern blot analysis of total splenic RNA. [MGI Ref ID J:79254]

Genotyping

Genotyping Information

Genotyping Protocols

Hmox1^tm1Poss, STD PCR, vers. 1

Helpful Links

Optimizing PCR Protocols

References

References

Selected Reference(s)

Poss KD; Tonegawa S. 1997. Heme oxygenase 1 is required for mammalian iron reutilization. Proc Natl Acad Sci U S A 94(20):10919-24. [PubMed: 9380735]  [MGI Ref ID J:79254]

Additional References

Hmox1^tm1Poss related

Ahmad AS; Zhuang H; Dore S. 2006. Heme oxygenase-1 protects brain from acute excitotoxicity. Neuroscience 141(4):1703-8. [PubMed: 16828975]  [MGI Ref ID J:113162]

Chen J; Tu Y; Moon C; Nagata E; Ronnett GV. 2003. Heme oxygenase-1 and heme oxygenase-2 have distinct roles in the proliferation and survival of olfactory receptor neurons mediated by cGMP and bilirubin, respectively. J Neurochem 85(5):1247-61. [PubMed: 12753084]  [MGI Ref ID J:83633]

Deshane J; Chen S; Caballero S; Grochot-Przeczek A; Was H; Li Calzi S; Lach R; Hock TD; Chen B; Hill-Kapturczak N; Siegal GP; Dulak J; Jozkowicz A; Grant MB; Agarwal A. 2007. Stromal cell-derived factor 1 promotes angiogenesis via a heme oxygenase 1-dependent mechanism. J Exp Med 204(3):605-18. [PubMed: 17339405]  [MGI Ref ID J:125359]

Ferris CD; Jaffrey SR; Sawa A; Takahashi M; Brady SD; Barrow RK; Tysoe SA; Wolosker H; Baranano DE; Dore S; Poss KD; Snyder SH. 1999. Haem oxygenase-1 prevents cell death by regulating cellular iron. Nat Cell Biol 1(3):152-7. [PubMed: 10559901]  [MGI Ref ID J:59677]

George JF; Braun A; Brusko TM; Joseph R; Bolisetty S; Wasserfall CH; Atkinson MA; Agarwal A; Kapturczak MH. 2008. Suppression by CD4+CD25+ regulatory T cells is dependent on expression of heme oxygenase-1 in antigen-presenting cells. Am J Pathol 173(1):154-60. [PubMed: 18511516]  [MGI Ref ID J:137311]

Kapturczak MH; Wasserfall C; Brusko T; Campbell-Thompson M; Ellis TM; Atkinson MA; Agarwal A. 2004. Heme oxygenase-1 modulates early inflammatory responses: evidence from the heme oxygenase-1-deficient mouse. Am J Pathol 165(3):1045-53. [PubMed: 15331427]  [MGI Ref ID J:92399]

Nath KA; Haggard JJ; Croatt AJ; Grande JP; Poss KD; Alam J. 2000. The indispensability of heme oxygenase-1 in protecting against acute heme protein-induced toxicity in vivo. Am J Pathol 156(5):1527-35. [PubMed: 10793064]  [MGI Ref ID J:108237]

Nath KA; d'Uscio LV; Juncos JP; Croatt AJ; Manriquez MC; Pittock ST; Katusic ZS. 2007. An analysis of the DOCA-salt model of hypertension in HO-1-/- mice and the Gunn rat. Am J Physiol Heart Circ Physiol 293(1):H333-42. [PubMed: 17351069]  [MGI Ref ID J:126038]

Orozco LD; Kapturczak MH; Barajas B; Wang X; Weinstein MM; Wong J; Deshane J; Bolisetty S; Shaposhnik Z; Shih DM; Agarwal A; Lusis AJ; Araujo JA. 2007. Heme oxygenase-1 expression in macrophages plays a beneficial role in atherosclerosis. Circ Res 100(12):1703-11. [PubMed: 17495224]  [MGI Ref ID J:137771]

Pittock ST; Norby SM; Grande JP; Croatt AJ; Bren GD; Badley AD; Caplice NM; Griffin MD; Nath KA. 2005. MCP-1 is up-regulated in unstressed and stressed HO-1 knockout mice: Pathophysiologic correlates. Kidney Int 68(2):611-22. [PubMed: 16014038]  [MGI Ref ID J:114303]

Shiraishi F; Curtis LM; Truong L; Poss K; Visner GA; Madsen K; Nick HS; Agarwal A. 2000. Heme oxygenase-1 gene ablation or expression modulates cisplatin-induced renal tubular apoptosis Am J Physiol Renal Physiol 278(5):F726-36. [PubMed: 10807584]  [MGI Ref ID J:62437]

Tracz MJ; Juncos JP; Grande JP; Croatt AJ; Ackerman AW; Rajagopalan G; Knutson KL; Badley AD; Griffin MD; Alam J; Nath KA. 2007. Renal hemodynamic, inflammatory, and apoptotic responses to lipopolysaccharide in HO-1-/- Mice. Am J Pathol 170(6):1820-30. [PubMed: 17525251]  [MGI Ref ID J:122077]

Tsuchihashi S; Livhits M; Zhai Y; Busuttil RW; Araujo JA; Kupiec-Weglinski JW. 2006. Basal rather than induced heme oxygenase-1 levels are crucial in the antioxidant cytoprotection. J Immunol 177(7):4749-57. [PubMed: 16982915]  [MGI Ref ID J:139311]

Wang J; Dore S. 2008. Heme oxygenase 2 deficiency increases brain swelling and inflammation after intracerebral hemorrhage. Neuroscience 155(4):1133-41. [PubMed: 18674596]  [MGI Ref ID J:140981]

Zelenay S; Chora A; Soares MP; Demengeot J. 2007. Heme oxygenase-1 is not required for mouse regulatory T cell development and function. Int Immunol 19(1):11-8. [PubMed: 17082514]  [MGI Ref ID J:118121]

Health & husbandry

Health & Colony Maintenance Information

Animal Health Reports

Room Number           AX11

Colony Maintenance

Breeding & Husbandry	When maintaining a live colony, these mice can be bred as heterozygotes. Fewer than expected or no homozygotes are produced from heterozygote crosses.
Mating System	Heterozygote x +/+ sibling         (Female x Male)
Diet Information	LabDiet® 5K52/5K67

Purchasing information

Pricing, Supply Level & Notes, Controls, General Terms & Conditions

Pricing

Supply Details

Standard Supply

Repository-Live. A collection of over 1000 strains maintained as live colonies. Individual colonies are sized to meet current customer demand. Delivery for orders of 10 mice or less ranges on average from one to eight weeks; mice are generally shipped between four to six weeks of age with a maximum shipping age of ~nine weeks. Colony sizes do not generally support stringent age specifications for large volumes of mice; however custom orders and larger quantities of mice are easily arranged. Estimated ship dates for all orders provided within 48 hours of order placement.

Supply Notes

Usually shipped between four and eight weeks of age. This strain is included in the Induced Mutant Resource Colony collection.

Control Information

	Control
	Wild-type from the colony
	001800 FVB/NJ
Considerations for Choosing Controls
USA, Canada and Mexico - Control Pricing Information for Genetically Engineered Mutant Strains.
International - Control Pricing Information for Genetically Engineered Mutant Strains.

General Terms and Conditions

See Terms of Use

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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Ordering and Purchasing Information

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Contact Information
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Tel: 800.422.6423 or 207.288.5845
Fax: 207.288.6150
Technical Support Email Form

Terms of Use

Terms of Use

General Terms and Conditions

For Licensing and Use Restrictions view the link(s) below:
- Use of MICE by companies or for-profit entities requires a license prior to shipping.

Contact information

General inquiries

Contracts Administration

phone:	207-288-6470
fax:	207-288-6655

JAX^® Mice & Services Conditions of Use

“Each recipient institution, including its employees and other researchers under its control (RECIPIENT), of mice or services using mice from The Jackson Laboratory (TJL) agrees that such mice, descendants of those mice derived by inbreeding or crossbreeding, including unmodified derivatives of those mice or their descendants (“MICE”) shall not be: (i) used for any purpose other than the internal research of the RECIPIENT, (ii) sold or otherwise provided to any third party for any use, or (iii) provided to any agent or other third party to provide breeding or other services with respect to MICE. Acceptance of MICE from TJL shall be deemed agreement by RECIPIENT to these conditions, and departure from these conditions requires The Jackson Laboratory’s prior written authorization.”

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