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 N?+6+N1p Generation Definitions   Donating Investigator M. Simon,   University of Pensylvania

Description
Arnt^-/- embryonic stem cells fail to activate genes that normally respond to low oxygen tension. They also fail to respond to a decrease in glucose concentration, indicating that ARNT is crucial in the response to hypoxia and to hypoglycaemia. Arnt^-/- embryos were not viable past embryonic day 10.5 and showed defective angiogenesis of the yolk sac and branchial arches, stunted development and embryo wasting. The defect in blood vessel formation in Arnt^-/- yolk sacs is similar to the angiogenic abnormalities reported for mice deficient in vascular endothelial growth factor or tissue factor.

Development
The exon encoding the basic-helix-loop-helis (bHLH) domain of the murine Arnt gene was disrupted by insertion of the phosphoglycerate kinase (PGK) promoter/neomycin-resistance cDNA.

Control Information

	Control
	000664 C57BL/6J
Considerations for Choosing Controls

Phenotype

Phenotype Information

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.

Arnt^tm1Mcs/Arnt^tm1Mcs

        involves: 129S1/Sv * 129X1/SvJ

• mortality/aging
• complete embryonic lethality
  • homozygous null embryos died by E10.5   (MGI Ref ID J:39730)
• cardiovascular system phenotype
• *normal* cardiovascular system phenotype
  • although extraembryonic vascularization was defective, the mutant heart, dorsal aorta and intersomitic vessels appeared normal   (MGI Ref ID J:39730)
• • abnormal angiogenesis
    • homozygous null embryos displayed defective angiogenesis of the yolk sac and branchial arches   (MGI Ref ID J:39730)
  • absent vitelline blood vessels
    • other mutant yolk sacs lacked large vitelline blood vessels and had enlarged capillaries instead   (MGI Ref ID J:39730)
  • disorganized yolk sac vascular plexus
    • in some mutant yolk sacs, there were fewer capillaries and these appeared to be fused with one another generating an abnormal vascular plexus   (MGI Ref ID J:39730)
• cellular phenotype
• *normal* cellular phenotype
  • mutant ES cells failed to activate genes that normally respond to low oxygen tension (hypoxia)   (MGI Ref ID J:39730)
  • mutant ES cells failed to respond to a decrease in glucose concentration (hypoglycemia)   (MGI Ref ID J:39730)
  • aggregation of mutant ES cells with tetraploid wild-type embryos rescued their placental defects; however, these embryos still died from yolk sac vascular and cardiac defects (reduced endocardial cushions, a hypoplastic ventricular myocardium, an enlarged atrioventricular canal, and distended dorsal aortae)   (MGI Ref ID J:66515)
• embryogenesis phenotype
• abnormal placenta development
  • mutant placentas contained no fetal vessels and were significantly smaller relative to wild-type   (MGI Ref ID J:66515)
• • abnormal chorionic plate morphology
    • although mutant endothelial cells entered the allantois and chorioallantoic fusion took place, mutant fetal blood vessels failed to invade the chorionic plate by E9.5   (MGI Ref ID J:66515)
• abnormal trophoblast layer morphology
  • mutant placentas showed poor trophoblast invasion of maternal myometrium, similar to preeclamptic human placentas   (MGI Ref ID J:66515)
• • abnormal spongiotrophoblast layer morphology
    • at E9.5, mutant placentas showed a severe reduction in diploid spongiotrophoblast cell numbers and a significant expansion in the giant cell population   (MGI Ref ID J:66515)
    • at E8.5, mutant placentas showed normal numbers of spongiotrophoblast cells that disappeared by E9.5 with no increase in TUNEL+ apoptotic cells, suggesting that spongiotrophoblasts themselves differentiated into giant cells at increased rates   (MGI Ref ID J:66515)
  • abnormal trophoblast giant cells
    • at E9.5, mutant placentas showed a severe reduction in diploid spongiotrophoblast cell numbers and a significant expansion in the giant cell population   (MGI Ref ID J:66515)
    • at E8.5, mutant placentas showed normal numbers of spongiotrophoblast cells that disappeared by E9.5 with no increase in TUNEL+ apoptotic cells, suggesting that spongiotrophoblasts themselves differentiated into giant cells at increased rates   (MGI Ref ID J:66515)
    • in contrast to wild-type, homozygous null trophoblast stem (TS) cells cultured under low oxygen tension failed to generate spongiotrophoblasts in vitro   (MGI Ref ID J:66515)
• abnormal visceral yolk sac morphology
  • at E9.5, many mutant yolk sacs contained normal blood islands but lacked normal vasculature   (MGI Ref ID J:39730)
  • mutant yolk sacs contained a reduced number of surrounding smooth muscle cells in vitelline vessels   (MGI Ref ID J:39730)
• • disorganized yolk sac vascular plexus
    • in some mutant yolk sacs, there were fewer capillaries and these appeared to be fused with one another generating an abnormal vascular plexus   (MGI Ref ID J:39730)
• absent placental labyrinth
  • complete loss of the labyrinthine layer resulted in decreased exchange between maternal and fetal circulations and subsequent intrauterine growth retardation   (MGI Ref ID J:66515)
• absent vitelline blood vessels
  • other mutant yolk sacs lacked large vitelline blood vessels and had enlarged capillaries instead   (MGI Ref ID J:39730)
• decreased embryo size
  • at E9.5, mutant embryos appeared smaller and generally wasted   (MGI Ref ID J:39730)
• embryonic growth retardation
  • at E9.5, mutant embryos appeared developmentally stunted   (MGI Ref ID J:39730)
  • notably, individual organ systems appeared morphologically normal relative to wild-type   (MGI Ref ID J:39730)
• growth/size phenotype
• decreased embryo size
  • at E9.5, mutant embryos appeared smaller and generally wasted   (MGI Ref ID J:39730)
• embryonic growth retardation
  • at E9.5, mutant embryos appeared developmentally stunted   (MGI Ref ID J:39730)
  • notably, individual organ systems appeared morphologically normal relative to wild-type   (MGI Ref ID J:39730)
• hematopoietic system phenotype
• impaired hematopoiesis
  • as early as E8.5, mutant embryos showed a significant decrease in the number of yolk sac hematopoietic progenitors   (MGI Ref ID J:70037)
  • this defect appeared to be cell extrinsic as homozygous null ES cells contributed competitively to all hematopoietic lineages in chimeric mice; also, the defect was associated with a reduction in ARNT-dependent VEGFA expression, and was reversed by exogenous VEGFA   (MGI Ref ID J:70037)

View Research Applications

Research Applications

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

Arnt^tm1Mcs related

Cardiovascular Research
Vascular Defects

Developmental Biology Research
Embryonic Lethality (Homozygous)

Metabolism Research

Genes & Alleles

Gene & Allele Information provided by MGI

Allele Symbol		Arnttm1Mcs
Allele Name		targeted mutation 1, M Celeste Simon
Allele Type		Targeted (knock-out)
Common Name(s)		Arnt(-); Arnt-;
Mutation Made By		M. Simon,   University of Pensylvania
Strain of Origin		(129X1/SvJ x 129S1/Sv)F1-Kitl<+>
ES Cell Line Name		R1
ES Cell Line Strain		(129X1/SvJ x 129S1/Sv)F1-Kitl<+>
Gene Symbol and Name		Arnt, aryl hydrocarbon receptor nuclear translocator
Chromosome		3
Gene Common Name(s)		Arnt1; D3Ertd557e; DNA segment, Chr 3, ERATO Doi 557, expressed; EST W08714; ESTM42; HIF-1-beta; HIF-1beta; HIF1-beta; HIF1B; HIF1BETA; TANGO; W08714; bHLHe2; expressed sequence tag mouse EST 42;
Molecular Note		A PGK-neomycin resistance cassette was inserted into the exon that encodes the basic-helix-loop-helix domain. [MGI Ref ID J:39730]

Genotyping

Genotyping Information

Genotyping Protocols

NEOTD (Generic Neo), Standard PCR

Helpful Links

Genotyping resources and troubleshooting

References

References provided by MGI

Selected Reference(s)

Maltepe E; Schmidt JV; Baunoch D; Bradfield CA; Simon MC. 1997. Abnormal angiogenesis and responses to glucose and oxygen deprivation in mice lacking the protein ARNT. Nature 386(6623):403-7. [PubMed: 9121557]  [MGI Ref ID J:39730]

Additional References

Arnt^tm1Mcs related

Adelman DM; Gertsenstein M; Nagy A; Simon MC; Maltepe E. 2000. Placental cell fates are regulated in vivo by HIF-mediated hypoxia responses Genes Dev 14(24):3191-203. [PubMed: 11124810]  [MGI Ref ID J:66515]

Adelman DM; Maltepe E; Simon MC. 1999. Multilineage embryonic hematopoiesis requires hypoxic ARNT activity. Genes Dev 13(19):2478-83. [PubMed: 10521392]  [MGI Ref ID J:70037]

Cowden Dahl KD; Fryer BH; Mack FA; Compernolle V; Maltepe E; Adelman DM; Carmeliet P; Simon MC. 2005. Hypoxia-inducible factors 1alpha and 2alpha regulate trophoblast differentiation. Mol Cell Biol 25(23):10479-91. [PubMed: 16287860]  [MGI Ref ID J:119854]

Cowden Dahl KD; Robertson SE; Weaver VM; Simon MC. 2005. Hypoxia-inducible factor regulates alphavbeta3 integrin cell surface expression. Mol Biol Cell 16(4):1901-12. [PubMed: 15689487]  [MGI Ref ID J:99217]

Keith B; Adelman DM; Simon MC. 2001. Targeted mutation of the murine arylhydrocarbon receptor nuclear translocator 2 (Arnt2) gene reveals partial redundancy with Arnt. Proc Natl Acad Sci U S A 98(12):6692-7. [PubMed: 11381139]  [MGI Ref ID J:69874]

Ramirez-Bergeron DL; Runge A; Adelman DM; Gohil M; Simon MC. 2006. HIF-dependent hematopoietic factors regulate the development of the embryonic vasculature. Dev Cell 11(1):81-92. [PubMed: 16824955]  [MGI Ref ID J:110805]

Health & husbandry

Health & Colony Maintenance Information

Animal Health Reports

Production of mice from cryopreserved embryos or sperm occurs in a maximum barrier room, RG10/RG30.

Colony Maintenance

Diet Information	LabDiet® 5K52/5K67

Purchasing information

Pricing, Supply Level & Notes, Controls

General Supply Notes

• This strain is included in the Induced Mutant Resource Colony collection.
• Genomic DNA is available for this strain from the Mouse DNA Resource.

Control Information

	Control
	000664 C57BL/6J
Considerations for Choosing Controls
Control Pricing Information for Genetically Engineered Mutant Strains.

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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.

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