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

View Genetics

Research Applications

Cardiovascular Research
Developmental Biology Research
Neurobiology Research

View All Research Applications

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

View All References

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

cardiovascular system phenotype

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

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

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

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

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

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 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

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

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

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

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

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

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

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

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

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

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

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

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

muscle phenotype

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

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

JAX® Mice, Products & Services Conditions of Use

"MICE" means mouse strains, their progeny derived by inbreeding or crossbreeding, unmodified derivatives from mouse strains or their progeny supplied by The Jackson Laboratory ("JACKSON"). "PRODUCT(S)" means biological materials supplied by JACKSON, and their derivatives. "SERVICES" means projects conducted by JACKSON for other parties that may include but are not limited to the use of MICE or PRODUCTS. "RECIPIENT" means each recipient of MICE, PRODUCTS, or SERVICES provided by JACKSON including each institution, its employees and other researchers under its control. MICE or PRODUCTS shall not be: (i) used for any purpose other than internal research, (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. Acceptance of MICE, PRODUCTS or SERVICES from JACKSON shall be deemed as agreement by RECIPIENT to these conditions, and departure from these conditions requires JACKSON’s prior written authorization.

No Warranty

MICE, PRODUCTS AND SERVICES ARE PROVIDED "AS IS". JACKSON EXTENDS NO WARRANTIES OF ANY KIND, EITHER EXPRESS, IMPLIED, OR STATUTORY, WITH RESPECT TO MICE, PRODUCTS OR SERVICES, INCLUDING ANY IMPLIED WARRANTY OF MERCHANTABILITY OR FITNESS FOR A PARTICULAR PURPOSE, OR ANY WARRANTY OF NON-INFRINGEMENT OF ANY PATENT, TRADEMARK, OR OTHER INTELLECTUAL PROPERTY RIGHTS.

Credit for PRODUCTS or SERVICES

In case of dissatisfaction for a valid reason and claimed in writing by a purchaser within ninety (90) days of receipt of, PRODUCTS or SERVICES, JACKSON will, at its option, provide credit or replacement for the PRODUCT received or the SERVICES provided; JACKSON makes no other representations and this shall be the exclusive remedy of the purchaser. Please note specific policy for live mice.

Animal Care and Use for SERVICES

Consistent with the requirement for a written understanding regarding animal care and use, the JACKSON Animal Care and Use Committee will review the animal care and use protocol(s) associated with any SERVICES to be performed at JACKSON, and JACKSON shall have ultimate responsibility and authority for the care of animals while on site or in JACKSON custody.

No Liability

In no event shall JACKSON, its trustees, directors, officers, employees, and affiliates be liable for any causes of action or damages, including any direct, indirect, special, or consequential damages, arising out of the provision of MICE, PRODUCTS, or SERVICES, including economic damage or injury to property and lost profits, and including any damage arising from acts or negligence on the part of JACKSON, its agents or employees. Unless prohibited by law, in purchasing or receiving MICE, PRODUCTS, or SERVICES from JACKSON, purchaser or recipient, or any party claiming by or through them, expressly releases and discharges JACKSON from all such causes of action or damages, and further agrees to defend and indemnify JACKSON from any costs or damages arising out of any third party claims.

MICE, PRODUCTS or SERVICES are to be used in a safe manner and in accordance with all applicable governmental rules and regulations.

The foregoing represents the General Terms and Conditions applicable to JACKSON’s MICE, PRODUCTS or SERVICES. In addition, special terms and conditions of sale of certain MICE, PRODUCTS, or SERVICES may be set forth separately in JACKSON web pages, catalogs, price lists, contracts, and/or other documents, and these special terms and conditions shall also govern the sale of these MICE, PRODUCTS and SERVICES by JACKSON, and by its licensees and distributors.

Acceptance of delivery of MICE, PRODUCTS or SERVICES shall be deemed agreement to these terms and conditions. No purchase order or other document transmitted by purchaser or recipient that may modify the terms and conditions hereof, shall be in any way binding on JACKSON, and instead the terms and conditions set forth herein, including any special terms and conditions set forth separately, shall govern the sale of MICE, PRODUCTS or SERVICES by JACKSON.

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

cardiovascular system phenotype

cellular phenotype

craniofacial phenotype

embryo phenotype

growth/size/body region phenotype

homeostasis/metabolism phenotype

mortality/aging

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

JAX® Mice, Products & Services Conditions of Use

No Warranty

Credit for PRODUCTS or SERVICES

Animal Care and Use for SERVICES

No Liability

Also Known As:Hif1a^-

Hif1a^tm1Jhu

Allele Symbol: Hif1a^tm1Jhu

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

Additional - Hif1a^tm1Jhu related