Overview

These Slc4a2 (or Ae2) knockout mice exhibit postnatal mortality (20%), with all dying by 40 days of age. Mice are emaciated, mildly ataxic, show evidence of dehydration, exhibit hearing loss and defective development of bone, and demonstrate a failure of both molar and incisor tooth eruption.

Donating Investigator

Gary E Shull, University of Cincinnati

Genetic overview

Genetic Background	Generation

Slc4a2^tm1Ges

Allele Type	Gene Symbol	Gene Name
Targeted (Null/Knockout)	Slc4a2	solute carrier family 4 (anion exchanger), member 2

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Research Applications

Internal/Organ Research
Neurobiology Research

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Details

Detailed Description

Homozygotes: A targeting vector was designed to replace exons 14-17 of the solute carrier family 4 (anion exchanger), member 2 (Slc9a4 or Ae2) gene with a neomycin resistance (neo) cassette, abolishing gene function. 20% of homozygous Ae2^-/- mice die postnatally, with all dying by 40 days of age. Ae2 is expressed in epithelial cells of the kidney, respiratory tract, and alimentary tract. Ae2 is required for HCO₃^- efflux and Cl^- influx across the basolateral membrane of gastric parietal cells, which are necessary for normal levels of gastric acid secretion. Ae2^-/- mice are emaciated, mildly ataxic, show evidence of dehydration, exhibit hearing loss and defective development of bone, and demonstrate a failure of both molar and incisor tooth eruption.

Heterozygote: Heterozygous mice are viable, fertile, and normal in size. They exhibit normal growth and are phenotypically similar to wildtype mice.

Development

A targeting vector was designed to replace exons 14-17 of the solute carrier family 4 (anion exchanger), member 2 (Slc9a4 or Ae2) gene with a neomycin resistance (neo) cassette. The construct was electroporated into 129S6/SvEvTac-derived embryonic stem (ES) cells and correctly targeted ES cells were injected into blastocysts. The resulting chimeric males were bred to Black Swiss females. This strain was maintained on a 129/Black Swiss background. Upon arrival at The Jackson Laboratory, mice were bred to 129S1/SvImJ inbred mice for at least one generation to establish the colony.

Control Suggestions

Wild-type from the colony

Additional Information

Considerations for Choosing Controls

Selected References

Gawenis LR; Ledoussal C; Judd LM; Prasad V; Alper SL; Stuart-Tilley A; Woo AL; Grisham C; Sanford LP; Doetschman T; Miller ML; Shull GE. 2004. Mice with a targeted disruption of the AE2 Cl-/HCO3- exchanger are achlorhydric. J Biol Chem 279(29):30531-9PubMed: 15123620 MGI: J:91617

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Genetics

Slc4a2^tm1Ges

Allele Symbol: Slc4a2^tm1Ges

Allele Name	targeted mutation 1, Gary E Shull
Allele Type	Targeted (Null/Knockout)
Allele Synonym(s)	AE2^-
Gene Symbol and Name	Slc4a2, solute carrier family 4 (anion exchanger), member 2
Gene Synonym(s)
Strain of Origin	129S6/SvEvTac
Chromosome	5
Molecular Note	A neo cassette replaced exons 14-17. Transcripts were expected to utilize the neo polyA, thereby lacking codons 703-1237, which encode the transmembrane domains. Northern blot using probes of sequences 3' to the neo showed that wild-type mRNAs were ablated in mutants, whereas probes of sequences 5' to the neo indicated presence of transcripts consistent in size with two splice variants. An immunofluorescence assay using an antibody that recognizes the C terminus confirmed protein disruption.
Mutations Made By	Gary Shull, University of Cincinnati

Disease/Phenotype

Disease Terms

Research Areas By Phenotype

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

Internal/Organ Research
- Skeleton
  - Bone
Neurobiology Research
- Channel and Transporter Defects
  - sodium/hydrogen
- Ataxia (Movement) 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: Slc4a2^tm1Ges/Slc4a2^tm1Ges
involves: 129S6/SvEvTac

skeleton phenotype

abnormal osteoclast physiology
- acidification of intracellular lysosomes is largely abrogated
- resting intracellular pH of cultured osteoclast like cells is more alkaline
- removal of bath Cl- does not change the intracellular pH of osteoclast like cells

abnormal osteoclast morphology
- actin belts in osteoclast like cells are thicker and individual podosomes are larger, more uniformly distributed and have a longer average lifespan
- osteoclasts have smaller ruffled borders that do not extend deep into the cytoplasm

hematopoietic system phenotype

abnormal osteoclast morphology
- osteoclasts have smaller ruffled borders that do not extend deep into the cytoplasm
- actin belts in osteoclast like cells are thicker and individual podosomes are larger, more uniformly distributed and have a longer average lifespan

abnormal osteoclast physiology
- removal of bath Cl- does not change the intracellular pH of osteoclast like cells
- acidification of intracellular lysosomes is largely abrogated
- resting intracellular pH of cultured osteoclast like cells is more alkaline

immune system phenotype

abnormal osteoclast morphology
- actin belts in osteoclast like cells are thicker and individual podosomes are larger, more uniformly distributed and have a longer average lifespan
- osteoclasts have smaller ruffled borders that do not extend deep into the cytoplasm

abnormal osteoclast physiology
- acidification of intracellular lysosomes is largely abrogated
- resting intracellular pH of cultured osteoclast like cells is more alkaline
- removal of bath Cl- does not change the intracellular pH of osteoclast like cells

The following phenotype relates to a compound genotype created using this strain

Genotype: Slc4a2^tm1Ges/Slc4a2^tm1Ges
involves: 129S6/SvEvTac * Black Swiss

behavior/neurological phenotype

aphagia
- about 10 - 15 days after birth homozygous pups stop eating

ataxia
- about 10 - 15 days after birth homozygous pups develop mild ataxia

endocrine/exocrine gland phenotype

abnormal gastric chief cell morphology
- fewer chief cells
- chief cells exhibit a reduction in the number of zymogen granules and a reduction in the amount of endoplasmic reticulum

abnormal gastric parietal cell morphology
- fewer parietal cells
- invaginations or interdigitations of the basolateral membrane is less compact and less regular than in wild-type and the volume density of mitochondria is decreased
- canalicular structures in the cytoplasm of parietal cells are greatly reduced in number

dilated gastric glands
- the lumens of the gastric glands are dilated with accumulation of basophilic material

growth/size/body region phenotype

decreased birth body size
- at birth 25% of the live homozygous pups are smaller than wild-type littermates

failure of tooth eruption
- about 10 - 15 days after birth homozygous pups display failure of both molar and incisor tooth eruption

postnatal growth retardation
- about 10 - 15 days after birth homozygous pups develop severe growth retardation

hearing/vestibular/ear phenotype

deafness
- severe hearing loss is seen

mortality/aging

premature death
- after 15 days of age homozygous pups display high morbidity and mortality with the oldest homozygote only reaching 40 days of age

perinatal lethality, incomplete penetrance
- at birth about 20% of homozygous pups are dead

postnatal lethality, incomplete penetrance
- after 15 days of age homozygous pups display high morbidity and mortality with the oldest homozygote only reaching 40 days of age

skeleton phenotype

failure of tooth eruption
- about 10 - 15 days after birth homozygous pups display failure of both molar and incisor tooth eruption

abnormal skeleton development
- abnormal bone development is seen

craniofacial phenotype

failure of tooth eruption
- about 10 - 15 days after birth homozygous pups display failure of both molar and incisor tooth eruption

digestive/alimentary phenotype

abnormal gastric chief cell morphology
- chief cells exhibit a reduction in the number of zymogen granules and a reduction in the amount of endoplasmic reticulum
- fewer chief cells

abnormal gastric parietal cell morphology
- fewer parietal cells
- canalicular structures in the cytoplasm of parietal cells are greatly reduced in number
- invaginations or interdigitations of the basolateral membrane is less compact and less regular than in wild-type and the volume density of mitochondria is decreased

abnormal stomach epithelium morphology
- moderate hyperkeratosis is seen in the non-glandular epithelium of the stomach

abnormal esophageal epithelium morphology
- moderate hyperkeratosis is seen in the epithelium of the esophagus

achlorhydria
- mutants fail to secrete gastric acid (achlorohydria)

dilated gastric glands
- the lumens of the gastric glands are dilated with accumulation of basophilic material

References

Gawenis LR; Ledoussal C; Judd LM; Prasad V; Alper SL; Stuart-Tilley A; Woo AL; Grisham C; Sanford LP; Doetschman T; Miller ML; Shull GE. 2004. Mice with a targeted disruption of the AE2 Cl-/HCO3- exchanger are achlorhydric. J Biol Chem 279(29):30531-9PubMed: 15123620 MGI: J:91617

Additional - Slc4a2^tm1Ges related

Technical Support

CONTACT TECHNICAL SUPPORT

Genotyping Protocols
- Separated PCR:Slc4a2
- Separated MCA:Slc4a2
- Genotyping resources and troubleshooting
Breeding Considerations

When maintaining a live colony, heterozygous mice may be bred to wildtype mice from the colony. Homozygous mice have no teeth and 20% die postnatally. All homozygotes die by 40 days of age.
- Additional Breeding and Husbandry Support
Citation
When using the STOCK Slc4a2^tm1Ges/Mmjax mouse strain in a publication, please cite the originating article(s) and include MMRRC stock #34267 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

Donating Investigator

Genetic overview

Research Applications

Detailed Description

Development

Control Suggestions

Additional Information

Selected References

Slc4a2tm1Ges

Allele Symbol: Slc4a2tm1Ges

Disease Terms

Research Areas By Phenotype

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

Mammalian Phenotype Terms by Genotype

Genotype: Slc4a2tm1Ges/Slc4a2tm1Gesinvolves: 129S6/SvEvTac

skeleton phenotype

hematopoietic system phenotype

immune system phenotype

Genotype: Slc4a2tm1Ges/Slc4a2tm1Gesinvolves: 129S6/SvEvTac * Black Swiss

behavior/neurological phenotype

endocrine/exocrine gland phenotype

growth/size/body region phenotype

hearing/vestibular/ear phenotype

mortality/aging

skeleton phenotype

craniofacial phenotype

digestive/alimentary phenotype

References

Additional - Slc4a2tm1Ges 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

Slc4a2^tm1Ges

Allele Symbol: Slc4a2^tm1Ges

Genotype: Slc4a2^tm1Ges/Slc4a2^tm1Ges
involves: 129S6/SvEvTac

Genotype: Slc4a2^tm1Ges/Slc4a2^tm1Ges
involves: 129S6/SvEvTac * Black Swiss

Additional - Slc4a2^tm1Ges related