Strain Name:

FVB.Cg-Slc12a2tm1Ges/Mmjax

Availability:

Cryopreserved - Ready for recovery     Available at the JAX MMRRC

Please refer to the Mutant Mouse Regional Resource Center (MMRRC) for information about FVB.Cg-Slc12a2tm1Ges/Mmjax MMRRC Stock Number 034262.
These Slc12a2 (or Nkcc1) knockout mice exhibit growth retardation with a 30% incidence of death by the time of weaning. They are deaf, have less body fat, reduced mean arterial blood pressure, exhibit reduced cAMP-induced short circuit currents in jejunum, cecum, and trachea, unusual head postures, and engage in circling behaviors and rapid spinning, but have difficulty maintaining their balance. These mice may be useful for studying the regulation of cell volume, and the control of Cl- and K+ secretion in the maintainance of hearing and blood pressure.

Description

The genotypes of the animals provided may not reflect those discussed in the strain description or the mating scheme utilized by The Jackson Laboratory prior to cryopreservation. Please inquire for possible genotypes for this specific strain.

Strain Information

Type Congenic; Mutant Strain; Targeted Mutation;
Additional information on Genetically Engineered and Mutant Mice.
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Additional information on Congenic nomenclature.
Specieslaboratory mouse
Generation+pN1
Generation Definitions
 
Donating Investigator Gary E Shull,   University of Cincinnati

Description
Homozygotes: A targeting vector was designed to insert a neomycin resistance (neo) cassette into exon 6 of the solute carrier family 12, member 2 (Slc12a2 or Nkcc1) gene, abolishing gene function. Homozygous mice are viable, fertile, and exhibit growth retardation with a 30% incidence of death by the time of weaning. Nkcc1 regulates cell volume and is expressed in vascular endothelial cells where it is required for controlling cytosolic concentrations of Cl- and K+, and in the basolateral membranes of epithelial cells where it provides an entry pathway for ions that are secreted across the apical membrane. These Nkcc1-/- mice are significantly smaller than their wildtype littermates by 1 week of age, and remain 80% smaller as adults. They are deaf, have less body fat, reduced mean arterial blood pressure, and exhibit reduced cAMP-induced short circuit currents in jejunum, cecum, and trachea. These mutant mice also demonstrate unusual head postures, and engage in circling behaviors and rapid spinning, but have difficulty maintaining their balance. The lumen of the cochlear duct of these mice is collapsed, and Reissner's membrane lies against the interdental cells of the spiral limbus, the tectorial membrane, and the stria vascularis. These mice may be useful for studying the regulation of cell volume, and the control of Cl- and K+ secretion in the maintainance of hearing and blood pressure.

Heterozygote: Heterozygous mice are viable, fertile, and normal in size. They exhibit normal growth, and are phenotypically similar to wildtype mice with the exception of slightly reduced blood pressure.

Development
A targeting vector was designed to insert a neomycin resistance (neo) cassette into exon 6 of the solute carrier family 12, member 2 (Slc12a2 or Nkcc1) 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 Information

  Control
   Wild-type from the colony
   001800 FVB/NJ (approximate)
 
  Considerations for Choosing Controls

Related Strains

Strains carrying other alleles of Slc12a2
002757   MK;B6-Slc12a2sy-ns/J
View Strains carrying other alleles of Slc12a2     (1 strain)

Phenotype

Phenotype Information

View Mammalian Phenotype Terms

Mammalian Phenotype Terms provided by MGI
      assigned by genotype

The following phenotype information may relate to a genetic background differing from this JAX® Mice strain.

Slc12a2tm1Ges/Slc12a2tm1Ges

        Background Not Specified
  • mortality/aging
  • partial postnatal lethality
    • incomplete penetrance; 30% dead by 3 weeks of age   (MGI Ref ID J:57651)
  • growth/size/body phenotype
  • decreased body size
    • although mutants gain weight after weaning, they remain smaller as adults than wild-type   (MGI Ref ID J:57651)
  • decreased total body fat amount   (MGI Ref ID J:57651)
  • postnatal growth retardation
    • incidence at 1-3 weeks; decreasing severity with age   (MGI Ref ID J:57651)
  • behavior/neurological phenotype
  • abnormal motor coordination/ balance   (MGI Ref ID J:57651)
  • absent pinna reflex   (MGI Ref ID J:57651)
  • circling   (MGI Ref ID J:57651)
  • head bobbing   (MGI Ref ID J:57651)
  • head tilt
    • head is tilted to one side or tilted upward and backward with the nose held high   (MGI Ref ID J:57651)
  • spinning   (MGI Ref ID J:57651)
  • hearing/vestibular/ear phenotype
  • abnormal ear physiology   (MGI Ref ID J:57651)
    • abnormal auditory brainstem response
      • The ABR wave form is not observed in mutants, even at 99 db   (MGI Ref ID J:57651)
    • deafness   (MGI Ref ID J:57651)
  • abnormal membranous labyrinth morphology
    • in the ampullae of the semicircular ducts, the membranous labyrinth is collapsed upon the cupula   (MGI Ref ID J:57651)
    • the membranous labyrinth in both the saccule and utricle is irregular and generally collapsed   (MGI Ref ID J:57651)
    • abnormal scala media morphology
      • the lumen of the cochlear duct is collapsed   (MGI Ref ID J:57651)
      • some mutants exhibit a wide scala media lumen   (MGI Ref ID J:57651)
      • abnormal stria vascularis morphology
        • the intercellular spaces between the marginal cell layer and deeper layers of the stria vascularis are wider than in wild-type   (MGI Ref ID J:57651)
        • abnormal strial marginal cell morphology
          • marginal cells lack the numerous basal processes seen in wild-type and are separated from basal and intermediate cells by intercellular spaces that are wider than in wild-type   (MGI Ref ID J:57651)
      • abnormal tectorial membrane morphology
        • accumulation of calcified crystalline material at the tectorial membrane   (MGI Ref ID J:57651)
      • absent tunnel of Corti
        • the tunnel of Corti is often absent in mutants   (MGI Ref ID J:57651)
      • decreased cochlear inner hair cell number
        • inner hair cells are identified only infrequently   (MGI Ref ID J:57651)
      • decreased cochlear outer hair cell number
        • outer hair cells are identified only infrequently   (MGI Ref ID J:57651)
  • collapsed Reissner membrane   (MGI Ref ID J:57651)
  • digestive/alimentary phenotype
  • abnormal intestine morphology
    • in young mice; decreasing severity with age   (MGI Ref ID J:57651)
    • abnormal colon morphology
      • frequent fecal blockage   (MGI Ref ID J:57651)
    • coiled cecum
      • worm-like appearance   (MGI Ref ID J:57651)
    • small intestinal prolapse   (MGI Ref ID J:57651)
  • decreased salivation   (MGI Ref ID J:64324)
  • remittent intestinal hemorrhage
    • incomplete penetrance   (MGI Ref ID J:57651)
  • cardiovascular system phenotype
  • decreased systemic arterial blood pressure   (MGI Ref ID J:57651)
  • remittent intestinal hemorrhage
    • incomplete penetrance   (MGI Ref ID J:57651)
  • endocrine/exocrine gland phenotype
  • decreased salivation   (MGI Ref ID J:64324)
  • adipose tissue phenotype
  • decreased total body fat amount   (MGI Ref ID J:57651)
  • nervous system phenotype
  • abnormal cranial ganglia morphology
    • reduced numbers of neuronal cell bodies in the spiral ganglion   (MGI Ref ID J:57651)
  • decreased cochlear inner hair cell number
    • inner hair cells are identified only infrequently   (MGI Ref ID J:57651)
  • decreased cochlear outer hair cell number
    • outer hair cells are identified only infrequently   (MGI Ref ID J:57651)
View Research Applications

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

Cell Biology Research
Channel and Transporter Defects
      chloride
      potassium

Developmental Biology Research
Growth Defects
      Growth Defects (homozygous)

Neurobiology Research
Channel and Transporter Defects
      potassium

Sensorineural Research
Hearing Defects

Genes & Alleles

Gene & Allele Information provided by MGI

 
Allele Symbol Slc12a2tm1Ges
Allele Name targeted mutation 1, Gary E Shull
Allele Type Targeted (knock-out)
Common Name(s) Nkcc1-;
Mutation Made By Gary Shull,   University of Cincinnati
Gene Symbol and Name Slc12a2, solute carrier family 12, member 2
Chromosome 18
Gene Common Name(s) BSC; BSC2; NKCC1; mBSC2; sodium/potassium/chloride cotransporters; sy-ns;
Molecular Note Insertion of a neomycin gene into exon 6. Northern blot analysis of brain, heart, skeletal muscle, lung, kidney, stomach, small intestine and colon failed to detect any mRNA in homozygous mutants. [MGI Ref ID J:57651]

Genotyping

Genotyping Information

Genotyping Protocols

Slc12a2tm1GesMCA,

Separated MCA


Slc12a2tm1Ges, Separated PCR


Helpful Links

Genotyping resources and troubleshooting

References

References provided by MGI

Selected Reference(s)

Flagella M; Clarke LL; Miller ML; Erway LC; Giannella RA; Andringa A; Gawenis LR; Kramer J; Duffy JJ; Doetschman T; Lorenz JN; Yamoah EN; Cardell EL; Shull GE. 1999. Mice lacking the basolateral Na-K-2Cl cotransporter have impaired epithelial chloride secretion and are profoundly deaf. J Biol Chem 274(38):26946-55. [PubMed: 10480906]  [MGI Ref ID J:57651]

Additional References

Slc12a2tm1Ges related

Bachmann O; Wuchner K; Rossmann H; Leipziger J; Osikowska B; Colledge WH; Ratcliff R; Evans MJ; Gregor M; Seidler U. 2003. Expression and regulation of the Na+-K+-2Cl- cotransporter NKCC1 in the normal and CFTR-deficient murine colon. J Physiol 549(Pt 2):525-36. [PubMed: 12692180]  [MGI Ref ID J:105419]

Castrop H; Lorenz JN; Hansen PB; Friis U; Mizel D; Oppermann M; Jensen BL; Briggs J; Skott O; Schnermann J. 2005. Contribution of the basolateral isoform of the Na-K-2Cl- cotransporter (NKCC1/BSC2) to renin secretion. Am J Physiol Renal Physiol 289(6):F1185-92. [PubMed: 16106034]  [MGI Ref ID J:115728]

Chen H; Luo J; Kintner DB; Shull GE; Sun D. 2005. Na(+)-dependent chloride transporter (NKCC1)-null mice exhibit less gray and white matter damage after focal cerebral ischemia. J Cereb Blood Flow Metab 25(1):54-66. [PubMed: 15678112]  [MGI Ref ID J:105268]

Evans RL; Park K; Turner RJ; Watson GE; Nguyen HV; Dennett MR; Hand AR; Flagella M; Shull GE; Melvin JE. 2000. Severe impairment of salivation in Na+/K+/2Cl- cotransporter (NKCC1)-deficient mice. J Biol Chem 275(35):26720-6. [PubMed: 10831596]  [MGI Ref ID J:64324]

Garg P; Martin CF; Elms SC; Gordon FJ; Wall SM; Garland CJ; Sutliff RL; O'Neill WC. 2007. Effect of the Na-K-2Cl cotransporter NKCC1 on systemic blood pressure and smooth muscle tone. Am J Physiol Heart Circ Physiol 292(5):H2100-5. [PubMed: 17259435]  [MGI Ref ID J:125943]

Gawenis LR; Hut H; Bot AG; Shull GE; de Jonge HR; Stien X; Miller ML; Clarke LL. 2004. Electroneutral sodium absorption and electrogenic anion secretion across murine small intestine are regulated in parallel. Am J Physiol Gastrointest Liver Physiol 287(6):G1140-9. [PubMed: 15284023]  [MGI Ref ID J:96161]

Hunt DL; Yamoah EN; Krubitzer L. 2006. Multisensory plasticity in congenitally deaf mice: How are cortical areas functionally specified? Neuroscience 139(4):1507-24. [PubMed: 16529873]  [MGI Ref ID J:108937]

Kim SM; Eisner C; Faulhaber-Walter R; Mizel D; Wall SM; Briggs JP; Schnermann J. 2008. Salt sensitivity of blood pressure in NKCC1-deficient mice. Am J Physiol Renal Physiol 295(4):F1230-8. [PubMed: 18701622]  [MGI Ref ID J:140586]

Koltsova SV; Kotelevtsev SV; Tremblay J; Hamet P; Orlov SN. 2009. Excitation-contraction coupling in resistance mesenteric arteries: evidence for NKCC1-mediated pathway. Biochem Biophys Res Commun 379(4):1080-3. [PubMed: 19150334]  [MGI Ref ID J:144985]

Meyer JW; Flagella M; Sutliff RL; Lorenz JN; Nieman ML; Weber CS; Paul RJ; Shull GE. 2002. Decreased blood pressure and vascular smooth muscle tone in mice lacking basolateral Na(+)-K(+)-2Cl(-) cotransporter. Am J Physiol Heart Circ Physiol 283(5):H1846-55. [PubMed: 12384462]  [MGI Ref ID J:108280]

Miller ML; Judd LM; Van Driel IR; Andringa A; Flagella M; Bell SM; Schultheis PJ; Spicer Z; Shull GE. 2002. The unique ultrastructure of secretory membranes in gastric parietal cells depends upon the presence of H+, K+ -ATPase. Cell Tissue Res 309(3):369-80. [PubMed: 12195293]  [MGI Ref ID J:105170]

Pech V; Thumova M; Kim YH; Agazatian D; Hummler E; Rossier BC; Weinstein AM; Nanami M; Wall SM. 2012. ENaC inhibition stimulates Cl- secretion in the mouse cortical collecting duct through an NKCC1-dependent mechanism. Am J Physiol Renal Physiol 303(1):F45-55. [PubMed: 22496413]  [MGI Ref ID J:187023]

Schobel N; Radtke D; Lubbert M; Gisselmann G; Lehmann R; Cichy A; Schreiner BS; Altmuller J; Spector AC; Spehr J; Hatt H; Wetzel CH. 2012. Trigeminal ganglion neurons of mice show intracellular chloride accumulation and chloride-dependent amplification of capsaicin-induced responses. PLoS One 7(11):e48005. [PubMed: 23144843]  [MGI Ref ID J:194953]

Shillingford JM; Miyoshi K; Flagella M; Shull GE; Hennighausen L. 2002. Mouse Mammary Epithelial Cells Express the Na-K-Cl Cotransporter, NKCC1: Characterization, Localization, and Involvement in Ductal Development and Morphogenesis. Mol Endocrinol 16(6):1309-21. [PubMed: 12040017]  [MGI Ref ID J:76874]

Sipila ST; Huttu K; Yamada J; Afzalov R; Voipio J; Blaesse P; Kaila K. 2009. Compensatory enhancement of intrinsic spiking upon NKCC1 disruption in neonatal hippocampus. J Neurosci 29(21):6982-8. [PubMed: 19474325]  [MGI Ref ID J:149517]

Wall SM; Knepper MA; Hassell KA; Fischer MP; Shodeinde A; Shin W; Pham TD; Meyer JW; Lorenz JN; Beierwaltes WH; Dietz JR; Shull GE; Kim YH. 2006. Hypotension in NKCC1 null mice: role of the kidneys. Am J Physiol Renal Physiol 290(2):F409-16. [PubMed: 16159893]  [MGI Ref ID J:104672]

Young Choi J; Ho Jung S; Namkung W; Lee JH; Jin Son E; Wook Shin J; Park HY; Sang Lee W; Kim HN. 2005. Vestibular malformation in mice lacking Na-K-2Cl cotransporter 1 and expression of Na-K-2Cl cotransporter 1 in human vestibular end organs. Acta Otolaryngol 125(12):1252-7. [PubMed: 16303670]  [MGI Ref ID J:125792]

Zheng W; Kuhlicke J; Jackel K; Eltzschig HK; Singh A; Sjoblom M; Riederer B; Weinhold C; Seidler U; Colgan SP; Karhausen J. 2009. Hypoxia inducible factor-1 (HIF-1)-mediated repression of cystic fibrosis transmembrane conductance regulator (CFTR) in the intestinal epithelium. FASEB J 23(1):204-13. [PubMed: 18779379]  [MGI Ref ID J:146039]

Health & husbandry

The genotypes of the animals provided may not reflect those discussed in the strain description or the mating scheme utilized by The Jackson Laboratory prior to cryopreservation. Please inquire for possible genotypes for this specific strain.

Health & Colony Maintenance Information

Animal Health Reports

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

Colony Maintenance

Breeding & HusbandryWhen maintaining a live colony, heterozygous mice may be bred to wildtype mice from the colony or to FVB/NJ inbred mice. Homozygous mice are runted and engage in circling behavior and rapid spinning. The donating investigator confirms that 30% of homozygotes die by 4 weeks of age.

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