Overview

Also Known As:Hif1a^-

HIF1 is a master regulator of homeostatic response to hypoxia. The Hif1a (hypoxia inducible factor 1, alpha subunit) knockout allele results in embryonic lethality by E11; embryos exhibit neural tube defects and cardiovascular malformations. On the diabetes-inducible FVB/N background, mice provide a tool for examining the role of hypoxia in diabetes.

Donating Investigator

Claudia Kappen, Pennington Biomedical Research Center

Genetic overview

Genetic Background	Generation

Hif1a^tm1Jhu

Allele Type	Gene Symbol	Gene Name
Targeted (Null/Knockout)	Hif1a	hypoxia inducible factor 1, alpha subunit

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Research Applications

Cardiovascular Research
Developmental Biology Research
Neurobiology Research

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Details

Detailed Description

Hif1a (hypoxia inducible factor 1, alpha subunit) encodes the alpha subunit of a heterodimer that functions as a master regulator of homeostatic response to hypoxia. HIF1 is essential to embryonic vascularization, tumor angiogenesis and ischemic disease.

Loss of HIF1A results in embryonic lethality by E11. Beginning at E8.5, some Hif1a null embryos appear abnormal, however, by E9 all null embryos are morphologically abnormal. Abnormal embryos are characterized by mesenchymal cell death resulting in failure of neural tube closure with cystic degeneration and prolapse of neural folds, hyperplasia of the presumptive myocardium, anomalous vascular structures in the cephalic mesenchyme, absent or hypoplastic branchial arch vessels, and abnormal dorsal aortae. Hif1a^tm1Jhu embryonic stem cells have reduced mRNA levels of glucose transporters, glycolytic enzymes, and vascular endothelial growth factor as well as impaired cellular proliferation.

On the FVB/N background streptozotocin (STZ) administration induces diabetes in Hif1a null mice providing a resource for examining the role of hypoxia in diabetes.

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. 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 a neomycin resistance cassette was used to replace exon 2. The construct was electroporated into 129S4/SvJae-derived J1 embryonic stem (ES) cells. Correctly targeted ES cells were injected into blastocysts. The resulting chimeric animals were bred to C57BL/6. Mice from the colony were transferred to Claudia Kappen at the Pennington Biomedical Research Institute and the allele was introgressed to FVB/N for at least 10 generations. Upon arrival, mice were bred to FVB/NJ for at least 1 generation to establish the colony.

Control Suggestions

001800 FVB/NJ

Additional Information

Considerations for Choosing Controls

Selected References

Iyer NV; Kotch LE; Agani F; Leung SW; Laughner E; Wenger RH; Gassmann M; Gearhart JD; Lawler AM; Yu AY; Semenza GL. 1998. Cellular and developmental control of O2 homeostasis by hypoxia-inducible factor 1 alpha. Genes Dev 12(2):149-62PubMed: 9436976 MGI: J:45554

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Genetics

Hif1a^tm1Jhu

Allele Symbol: Hif1a^tm1Jhu

Allele Name	targeted mutation 1, Johns Hopkins University
Allele Type	Targeted (Null/Knockout)
Allele Synonym(s)	Hif1a^-
Gene Symbol and Name	Hif1a, hypoxia inducible factor 1, alpha subunit
Gene Synonym(s)
Strain of Origin	129S4/SvJae
Chromosome	12
Molecular Note	A neomycin resistance cassette replaced exon 2, which encodes the bHLH domain, of the gene.

Disease/Phenotype

Disease Terms

Research Areas By Phenotype

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

Cardiovascular Research
- Vascular Defects
Developmental Biology Research
- Neural Tube Defects
- Embryonic Lethality (Homozygous)
Neurobiology Research
- Neural Tube Defects

Mammalian Phenotype Terms by Genotype

The following phenotype information is associated with a similar, but not exact match to this JAX^® Mice strain

Genotype: Hif1a^tm1Jhu/Hif1a^tm1Jhu
involves: 129S4/SvJae * C57BL/6

cellular phenotype

increased apoptosis
- at E8.5, homozygotes exhibit excessive cell death prior to the onset of any vascular defects (not shown)

craniofacial phenotype

absent pharyngeal arch arteries
- by E9.25, mutant branchial arch vessels are either severely hypoplastic or absent

pharyngeal arch artery hypoplasia
- by E9.25, mutant branchial arch vessels are either severely hypoplastic or absent

embryo phenotype

incomplete somite formation
- at E9.75-E10.0, wild-type embryos have a mean of 29 somites, whereas homozygous mutant embryos have a mean of 12 somites

embryonic growth arrest
- homozygotes begin to display a developmental arrest late at E8, with striking differences noted by E10.0

open neural tube
- prolapse of the lateral neural folds is associated with buckling of the somatic ectoderm ventral to the neurosomatic junction
- by E10.0, homozygotes exhibit failure of neural tube closure with cystic degeneration and prolapse of the neural folds

pharyngeal arch artery hypoplasia
- by E9.25, mutant branchial arch vessels are either severely hypoplastic or absent

absent pharyngeal arch arteries
- by E9.25, mutant branchial arch vessels are either severely hypoplastic or absent

abnormal head mesenchyme morphology
- at E9.75-E10.0, homozygotes display extensive mesenchymal cell death in the cranial region, leading to an open neural tube

growth/size/body region phenotype

abnormal head mesenchyme morphology
- at E9.75-E10.0, homozygotes display extensive mesenchymal cell death in the cranial region, leading to an open neural tube

homeostasis/metabolism phenotype

pericardial effusion
- by E10.0, homozygotes display pericardial effusion

mortality/aging

embryonic lethality during organogenesis, complete penetrance
- dead (asystolic) homozygotes are first detected at E10.0; no homozygotes survive beyond E11.0

cardiovascular system phenotype

abnormal dorsal aorta morphology
- at E9.25, mutant dorsal aortae exhibit aberrant morphology with localized regions of dilatation
- by E9.75, all homozygotes show abnormalities in the diameter and/or position of the dorsal aortae

abnormal vascular development
- homozygotes display proper vascularization at E8.5 but exhibit enlarged vascular structures and absence of normal cephalic vascularization by E9.25

absent pharyngeal arch arteries
- by E9.25, mutant branchial arch vessels are either severely hypoplastic or absent

pericardial effusion
- by E10.0, homozygotes display pericardial effusion

abnormal pericardium morphology
- at E9.75-E10.0, homozygotes display abnormal endothelial-lined vascular structures within the enlarged pericardial cavity and along the pericardium

abnormal heart ventricle morphology

abnormal intersomitic vessel morphology
- by E9.75, all homozygotes show abnormalities in the diameter and/or position of the intersomitic vessels

abnormal pericardial cavity morphology
- at E9.75-E10.0, homozygotes exhibit enlarged pericardial cavity

abnormal myocardium layer morphology
- at E9.75-E10.0, homozygotes display hyperplasia of the presumptive myocardium

disorganized myocardium
- at E9.75, homozygotes exhibit a highly disorganized presumptive myocardium, with as many as 12 concentric cell layers in some regions relative to the 2-3 cell layers found in wild-type

pharyngeal arch artery hypoplasia
- by E9.25, mutant branchial arch vessels are either severely hypoplastic or absent

abnormal cardiac outflow tract development
- 21% of E9.25 and 40% of E9.75 homozygotes exhibit a significantly reduced outflow tract

abnormal blood vessel morphology
- at E9.75-E10.0, homozygotes exhibit only a sparse network of small vessels, with massively enlarged endothelial-lined vascular structures predominantly in the cephalic region, and along the path of dorsal aortae

dilated dorsal aorta
- localized regions of dilatation at E9.25

abnormal heart tube morphology
- at E9.75, mutant heart tubes show absence of a patent lumen

muscle phenotype

disorganized myocardium
- at E9.75, homozygotes exhibit a highly disorganized presumptive myocardium, with as many as 12 concentric cell layers in some regions relative to the 2-3 cell layers found in wild-type

abnormal myocardium layer morphology
- at E9.75-E10.0, homozygotes display hyperplasia of the presumptive myocardium

nervous system phenotype

increased hindbrain size
- by E10.0, homozygotes display cystic enlargement of the hindbrain

open neural tube
- by E10.0, homozygotes exhibit failure of neural tube closure with cystic degeneration and prolapse of the neural folds
- prolapse of the lateral neural folds is associated with buckling of the somatic ectoderm ventral to the neurosomatic junction

References

Iyer NV; Kotch LE; Agani F; Leung SW; Laughner E; Wenger RH; Gassmann M; Gearhart JD; Lawler AM; Yu AY; Semenza GL. 1998. Cellular and developmental control of O2 homeostasis by hypoxia-inducible factor 1 alpha. Genes Dev 12(2):149-62PubMed: 9436976 MGI: J:45554

Additional - Hif1a^tm1Jhu related

Technical Support

CONTACT TECHNICAL SUPPORT

Genotyping Protocols
- Standard PCR:Hif1aAlternate2
- Genotyping resources and troubleshooting
Breeding Considerations

While maintaining a live colony, these mice are bred as heterozygotes. Mice homozygous for the mutation are not viable.
- Additional Breeding and Husbandry Support
Citation
When using the Hif1a^- mouse strain in a publication, please cite the originating article(s) and include MMRRC stock #37489 in your Materials and Methods section.

Animal Health Reports

Facility Barrier Level Descriptions

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

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. We do not guarantee breeding performance and therefore suggest that investigators order more than one breeding pair to avoid delays in their research.

Terms Of Use

General Terms and Conditions

See MMRRC for Additional Conditions of Distribution

Questions about Terms of Use

Licensing Information

Phone: 207-288-6470

Email: TechTran@jax.org

Also Known As:Hif1a-

Donating Investigator

Genetic overview

Research Applications

Detailed Description

Development

Control Suggestions

Additional Information

Selected References

Hif1atm1Jhu

Allele Symbol: Hif1atm1Jhu

Disease Terms

Research Areas By Phenotype

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

Mammalian Phenotype Terms by Genotype

Genotype: Hif1atm1Jhu/Hif1atm1Jhuinvolves: 129S4/SvJae * C57BL/6

cellular phenotype

craniofacial phenotype

embryo phenotype

growth/size/body region phenotype

homeostasis/metabolism phenotype

mortality/aging

cardiovascular system phenotype

muscle phenotype

nervous system phenotype

References

Additional - Hif1atm1Jhu related

Genotyping Protocols

Breeding Considerations

Citation

Animal Health Reports

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

The Jackson Laboratory's Genotype Promise

Terms Of Use

Licensing Information

Also Known As:Hif1a^-

Hif1a^tm1Jhu

Allele Symbol: Hif1a^tm1Jhu

Genotype: Hif1a^tm1Jhu/Hif1a^tm1Jhu
involves: 129S4/SvJae * C57BL/6

Additional - Hif1a^tm1Jhu related