Overview

Also Known As:Nhe1-

These Slc9a knockout mice exhibit decreased postnatal growth with ataxic gait, epileptic-like seizures, increased mortality, thin skin, thickening of the lamina propria and slight atrophic glandular mucosa in the stomach. These mice may be useful for studying postnatal cell proliferation.

Donating Investigator

Gary E Shull, University of Cincinnati

Genetic overview

Genetic Background	Generation

Slc9a1^tm1Smb

Allele Type	Gene Symbol	Gene Name
Targeted (Null/Knockout)	Slc9a1	solute carrier family 9 (sodium/hydrogen exchanger), member 1

View Genetics

Research Applications

Cell Biology Research
Developmental Biology Research
Endocrine Deficiency Research
Neurobiology Research

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Details

Detailed Description

Homozygotes: A targeting vector was designed to insert a neomycin resistance (neo) cassette into the 3' end of exon 2 of the solute carrier family 9 (sodium/hydrogen exchanger), member 1 (Slc9a1 or Nhe1) gene, abolishing gene function. Nhe1 is expressed in the hippocampus, periamygdaloid cortex, and cerebellum, and is a key regulator of pH homeostasis, cell volume, and the proliferative response to growth factor stimulation. Homozygous Nhe1^-/- mice are viable and indistinguishable from their littermates through the first week of age. These mice show decreased postnatal growth with ataxic gait and epileptic-like seizures at 2 weeks of age. Mortality of homozygous mutant mice is increased to 68% by 29 days of age, with a reduction to 10% under low stress conditions. Postmortem animals exhibit a waxy particulate in the ears, around the eyes and chin, and on the ventral surface of the paws. The thickness of the skin, including the epidermis, dermis, subcutaneous fat, and muscle is significantly thinner in these mutant mice. These mice also display thickening of the lamina propria and slight atrophic glandular mucosa in the stomach. These mice may be useful for studying postnatal cell proliferation and similarities between the Nhe^-/- mutation and the spontaneous swe mutation within the Nhe locus.

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 insert a neomycin resistance (neo) cassette into the 3' end of exon 2 of the solute carrier family 9 (sodium/hydrogen exchanger), member 1 (Slc9a1 or Nhe1) gene. The construct was electroporated into 129-derived embryonic stem (ES) cells and correctly targeted ES cells were injected into C57BL/6 blastocysts. The resulting chimeric males were bred to Black Swiss females, and these mice were subsequently backcrossed to FVB/N mice for at least 10 generations. Upon arrival at The Jackson Laboratory, mice were bred to FVB/NJ inbred mice for at least one generation to establish the colony.

Control Suggestions

Wild-type from the colony

Approximate Controls

001800 FVB/NJ

Additional Information

Considerations for Choosing Controls

Selected References

Bell SM; Schreiner CM; Schultheis PJ; Miller ML; Evans RL; Vorhees CV; Shull GE; Scott WJ. 1999. Targeted disruption of the murine Nhe1 locus induces ataxia, growth retardation, and seizures. Am J Physiol 276(4 Pt 1):C788-95PubMed: 10199808 MGI: J:54705

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Genetics

Slc9a1^tm1Smb

Allele Symbol: Slc9a1^tm1Smb

Allele Name	targeted mutation 1, Sheila M Bell
Allele Type	Targeted (Null/Knockout)
Allele Synonym(s)	Nhe1 -; Nhe1^-
Gene Symbol and Name	Slc9a1, solute carrier family 9 (sodium/hydrogen exchanger), member 1
Gene Synonym(s)
Strain of Origin	Not Specified
Chromosome	4
Molecular Note	A portion of exon 2 was replaced by a neomycin selection cassette inserted by homologous recombination. The deleted region encoded transmembrane domains 6 and 7 (amino acids 217 through 275). Two aberrant transcripts were detected in mutant mice by Northern blot and RT-PCR analyses. Analysis indicated that a 613 bp transcript resulted from readthrough of the neo cassette and a 380 bp transcript underwent splicing of codon 198 to exon 3. Biochemical analysis, based on pH recover after an acute acid load, of acinar cells indicated a functional ablation of the endogenous protein.
Mutations Made By	Shelia Bell, Children's Hospital of Cincinnati

Disease/Phenotype

Disease Terms

Research Areas By Phenotype

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

Cell Biology Research
- Genes Regulating Growth and Proliferation
Developmental Biology Research
- Growth Defects
  - Growth Defects (homozygous)
- Postnatal Lethality
  - Homozygous
Endocrine Deficiency Research
- Skin Defects
Neurobiology Research
- 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: Slc9a1^tm1Smb/Slc9a1^tm1Smb
involves: 129X1/SvJ * Black Swiss

behavior/neurological phenotype

ataxia
- at 2 weeks, homozygotes begin to exhibit an ataxic gait that results in inability to move the hindlimbs

convulsive seizures
- at 2 weeks, homozygotes display preconvulsant episodes that often end in a catatonic-like state resembling an absence seizure
- at death, homozygotes display a postmortem appearance suggestive of death by a convulsive seizure (forepaws in flexion)

decreased exploration in new environment
- when placed in a novel environment, homozygotes appear hesitant to move and explore their surroundings

poor grooming
- such material is not observed on living mutants, suggesting lack of normal grooming by the mutants prior to death
- within 16 hours of death, homozygotes exhibit varying degrees of a wax-like material primarily on the ventral surface of paws, around the eyes, inside the ear, on the chin, and within the back fur

digestive/alimentary phenotype

abnormal parotid gland physiology
- mutant parotid saliva shows a significant increase in osmolality and sodium, potassium, and chloride content, indicating impaired NaCl absorption
- Na+/H+ exchanger activity is reduced >95% in acinar cells and >80% in duct cells isolated from mutant parotid glands

abnormal stomach glandular epithelium morphology
- homozygotes have a widened lamina propria between the gastric glands and at the base of gastric epithelium
- mutant gastric glands show a decrease in thickness of the whole gastric epithelium

decreased salivation
- also, homozygotes show a significant reduction in the rate of saliva secretion: the flow rate reaches a 42% inhibition at the end of the 50-min period
- relative to wild-type, homozygotes show a 34% reduction in the total volume of pilocarpine-stimulated saliva secreted over a 50-min collection period

endocrine/exocrine gland phenotype

abnormal parotid gland physiology
- mutant parotid saliva shows a significant increase in osmolality and sodium, potassium, and chloride content, indicating impaired NaCl absorption
- Na+/H+ exchanger activity is reduced >95% in acinar cells and >80% in duct cells isolated from mutant parotid glands

decreased salivation
- also, homozygotes show a significant reduction in the rate of saliva secretion: the flow rate reaches a 42% inhibition at the end of the 50-min period
- relative to wild-type, homozygotes show a 34% reduction in the total volume of pilocarpine-stimulated saliva secreted over a 50-min collection period

growth/size/body region phenotype

decreased body weight
- at 2 weeks, homozygotes display a significant reduction in body weight relative to wild-type
- by 10 weeks, homozygotes weigh only ~18 g in contrast to the ~28 g characteristic of wild-type mice

homeostasis/metabolism phenotype

decreased response of heart to induced stress
- amage and LDH release and higher left ventricular ATP content relative to wild-type hearts
- in the absence of an NHE1 inhibitor (eniporide), homozygotes are resistant to cardiac ischemia-reperfusion injury with significantly less impaired left ventricular developed pressure, end-diastolic pressure, and coronary flow as well as reduced cellular damage and LDH release and higher left ventricular ATP content relative to wild-type hearts
- notably, eniporide has no apparent effect on the degree of cardioprotection observed in mutant hearts

decreased salivation
- also, homozygotes show a significant reduction in the rate of saliva secretion: the flow rate reaches a 42% inhibition at the end of the 50-min period
- relative to wild-type, homozygotes show a 34% reduction in the total volume of pilocarpine-stimulated saliva secreted over a 50-min collection period

integument phenotype

abnormal epidermis stratum corneum morphology
- homozygotes show a slight increase in keratin accumulation with small lipid droplets on the surface of the cornified layer
- these particles are roughly the same size as the small particles found on mutant skin

thin skin
- within 16 hours of death, homozygotes exhibit reduced thickness of the whole skin, including the epidermis, dermis, subcutaneous fat, and muscle

mammalian phenotype

endocrine/exocrine gland phenotype
- Normal - homozygotes display normal parotid gland weight and morphology relative to wild-type
- Normal - however, in response to chronic beta1-adrenergic receptor stimulation, homozygotes show an isoproterenol-induced parotid gland hypertrophy in acinar cells that is comparable to that observed in wild-type
- Normal - parotid acinar cells from isoproterenol-treated homozygotes lack Na+/H+ exchanger activity

homeostasis/metabolism phenotype
- Normal - homozygotes display normal systemic acid-base homeostasis (pH, PCO2, PO2, and HCO-3) relative to wild-type

nervous system phenotype
- Normal - homozygotes show no changes in the appearance or number of Purkinje or granule cells of the folia of the cerebellum; the molecular layer is of normal thickness

mortality/aging

lethality at weaning, incomplete penetrance
- about 68% of homozygotes die beginning on P16-P18 and through P29

nervous system phenotype

convulsive seizures
- at 2 weeks, homozygotes display preconvulsant episodes that often end in a catatonic-like state resembling an absence seizure
- at death, homozygotes display a postmortem appearance suggestive of death by a convulsive seizure (forepaws in flexion)

reproductive system phenotype

abnormal fertility/fecundity
- female homozygotes mated with male heterozygotes are able to carry a litter to term; however, females that deliver subsequently die several days postpartum
- homozygotes that reach adulthood are fertile and capable of breeding with wild-type or heterozygous mice
- no successful matings between male homozygotes and female homozygotes are observed

cardiovascular system phenotype

decreased heart weight
- homozygotes exhibit significantly lower heart weights relative to wild-type mice
- however, no significant differences in mean HW/BW ratios are observed with or without eniporide treatment, suggesting that smaller hearts are a result of growth retardation

decreased response of heart to induced stress
- amage and LDH release and higher left ventricular ATP content relative to wild-type hearts
- in the absence of an NHE1 inhibitor (eniporide), homozygotes are resistant to cardiac ischemia-reperfusion injury with significantly less impaired left ventricular developed pressure, end-diastolic pressure, and coronary flow as well as reduced cellular damage and LDH release and higher left ventricular ATP content relative to wild-type hearts
- notably, eniporide has no apparent effect on the degree of cardioprotection observed in mutant hearts

References

Bell SM; Schreiner CM; Schultheis PJ; Miller ML; Evans RL; Vorhees CV; Shull GE; Scott WJ. 1999. Targeted disruption of the murine Nhe1 locus induces ataxia, growth retardation, and seizures. Am J Physiol 276(4 Pt 1):C788-95PubMed: 10199808 MGI: J:54705

Additional - Slc9a1^tm1Smb related

Technical Support

CONTACT TECHNICAL SUPPORT

Genotyping Protocols
- Separated PCR:Slc9a1
- Genotyping resources and troubleshooting
Breeding Considerations

When maintaining a live colony, heterozygous mice may be bred to wildtype mice from the colony or FVB/NJ inbred mice. The Donating Investigator confirms mortality rate of homozygotes is 68% by 29 days of age, with a reduction to 10% under low stress conditions.
- Additional Breeding and Husbandry Support
Citation
When using the Nhe1- mouse strain in a publication, please cite the originating article(s) and include MMRRC stock #34264 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.

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Questions about Terms of Use

Licensing Information

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Also Known As:Nhe1-

Donating Investigator

Genetic overview

Research Applications

Detailed Description

Development

Control Suggestions

Approximate Controls

Additional Information

Selected References

Slc9a1tm1Smb

Allele Symbol: Slc9a1tm1Smb

Disease Terms

Research Areas By Phenotype

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

Mammalian Phenotype Terms by Genotype

Genotype: Slc9a1tm1Smb/Slc9a1tm1Smbinvolves: 129X1/SvJ * Black Swiss

behavior/neurological phenotype

digestive/alimentary phenotype

endocrine/exocrine gland phenotype

growth/size/body region phenotype

homeostasis/metabolism phenotype

integument phenotype

mammalian phenotype

mortality/aging

nervous system phenotype

reproductive system phenotype

cardiovascular system phenotype

References

Additional - Slc9a1tm1Smb 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

Slc9a1^tm1Smb

Allele Symbol: Slc9a1^tm1Smb

Genotype: Slc9a1^tm1Smb/Slc9a1^tm1Smb
involves: 129X1/SvJ * Black Swiss

Additional - Slc9a1^tm1Smb related