Description

Strain Information

Type Congenic; Mutant Strain; Targeted Mutation; Additional information on Genetically Engineered Mutant Mice. Species laboratory mouse Generation N?+6+N1p   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

Additional Web Information

Congenic Nomenclature

Phenotype

Phenotype Information

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.

Arnt^tm1Mcs/Arnt^tm1Mcs

        involves: 129S1/Sv * 129X1/SvJ

• lethality-prenatal/perinatal
• embryonic lethality during organogenesis (MGI Ref ID J:39730)
  • homozygous null embryos died by E10.5
• cardiovascular system phenotype
• *normal* cardiovascular system phenotype (MGI Ref ID J:39730)
  • although extraembryonic vascularization was defective, the mutant heart, dorsal aorta and intersomitic vessels appeared normal
• abnormal angiogenesis (MGI Ref ID J:39730)
  • homozygous null embryos displayed defective angiogenesis of the yolk sac and branchial arches
• cellular phenotype
• *normal* cellular phenotype (MGI Ref ID J:39730)
  • mutant ES cells failed to activate genes that normally respond to low oxygen tension (hypoxia)
  • mutant ES cells failed to respond to a decrease in glucose concentration (hypoglycemia)
  • 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)
• embryogenesis phenotype
• abnormal placenta development (MGI Ref ID J:66515)
  • mutant placentas contained no fetal vessels and were significantly smaller relative to wild-type
• abnormal chorionic plate morphology (MGI Ref ID J:66515)
  • 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
• abnormal spongiotrophoblast layer morphology (MGI Ref ID J:66515)
  • at E9.5, mutant placentas showed a severe reduction in diploid spongiotrophoblast cell numbers and a significant expansion in the giant cell population
  • 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
• abnormal trophoblast layer morphology (MGI Ref ID J:66515)
  • mutant placentas showed poor trophoblast invasion of maternal myometrium, similar to preeclamptic human placentas
• abnormal trophoblast giant cells (MGI Ref ID J:66515)
  • at E9.5, mutant placentas showed a severe reduction in diploid spongiotrophoblast cell numbers and a significant expansion in the giant cell population
  • 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
  • in contrast to wild-type, homozygous null trophoblast stem (TS) cells cultured under low oxygen tension failed to generate spongiotrophoblasts in vitro
• abnormal yolk sac morphology (MGI Ref ID J:39730)
  • at E9.5, many mutant yolk sacs contained normal blood islands but lacked normal vasculature
  • mutant yolk sacs contained a reduced number of surrounding smooth muscle cells in vitelline vessels
• absent vitelline blood vessels (MGI Ref ID J:39730)
  • other mutant yolk sacs lacked large vitelline blood vessels and had enlarged capillaries instead
• disorganized vascular plexus (MGI Ref ID J:39730)
  • in some mutant yolk sacs, there were fewer capillaries and these appeared to be fused with one another generating an abnormal vascular plexus
• absent placental labyrinth (MGI Ref ID J:66515)
  • complete loss of the labyrinthine layer resulted in decreased exchange between maternal and fetal circulations and subsequent intrauterine growth retardation
• embryonic growth retardation (MGI Ref ID J:39730)
  • at E9.5, mutant embryos appeared developmentally stunted
  • notably, individual organ systems appeared morphologically normal relative to wild-type
• reduced embryo size (MGI Ref ID J:39730)
  • at E9.5, mutant embryos appeared smaller and generally wasted
• growth/size phenotype
• embryonic growth retardation (MGI Ref ID J:39730)
  • at E9.5, mutant embryos appeared developmentally stunted
  • notably, individual organ systems appeared morphologically normal relative to wild-type
• reduced embryo size (MGI Ref ID J:39730)
  • at E9.5, mutant embryos appeared smaller and generally wasted
• hematopoietic system phenotype
• impaired hematopoiesis (MGI Ref ID J:70037)
  • as early as E8.5, mutant embryos showed a significant decrease in the number of yolk sac hematopoietic progenitors
  • 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

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

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-1beta; 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), STD PCR, vers. 1

Helpful Links

Optimizing PCR Protocols

References

References

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]

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

Colony Maintenance

Diet Information	LabDiet® 5K52/5K67

Purchasing information

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

Pricing

Supply Details

Standard Supply

Repository-Cryopreserved. Must Be Recovered. Please refer to pricing and supply notes for further information.

Supply Notes

Cryorecovery - Standard. The recovery process begins when a signed agreement form is returned to the Customer Service Department after order placement. Although results vary by strain, at least two males and two females (two pairs) will be provided, typically within 15 weeks of our receipt of the signed agreement form. If the first recovery attempt is unsuccessful or only one pair is recovered, a second recovery will be done, extending the delivery time to approximately 25 weeks. At least one member of each pair will be of known genotype and will carry the mutation if it is a mutant strain. Please note that pairs may not reflect the mating scheme utilized by The Jackson Laboratory prior to cryopreservation of the strain. Mating schemes are sometimes modified for successful cryopreservation. Price represents a repository maintenance fee, which includes the cost of recovery of the strain from the cryopreservation resource and the periodic replacement of the frozen embryos used for recovery. Cryorecovery to establish a Dedicated Supply for greater quantities of mice. One to two pairs will be recovered to establish a Dedicated Supply of mice. Price by quotation. For more information on Dedicated Supply, please contact JAX® Services, Tel: 1-800-422-6423 or 1-207-288-5845. 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
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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phone:	207-288-6470
fax:	207-288-6655

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“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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