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. Visit our online Nomenclature tutorial. Additional information on Congenic nomenclature. Species laboratory mouse Generation F2pN1 Generation Definitions   Donating Investigator Gary E Shull,   University of Cincinnati

Description
These mice harbor a targeted mutation of the Na⁺/H⁺ exchanger isoform 3 locus (Nhe3 or Slc9a3) that abolishes endogenous gene expression. While no full-length mRNA is detected in kidney or intestine of homozygous mice, a truncated mutant mRNA lacking codons 320-831 (encoding sequences required for Na⁺/H⁺ exchange) is observed but expected to impart no dominant negative effects. When maintained as congenic on the FVB/N genetic background, homozygous mice exhibit a high mortality rate beginning just after weaning, with ~30% surviving to adulthood. Homozygous females are fertile, but homozygous males are infertile.
Homozygous (Nhe3-null) mice lack Na⁺/H⁺ exchanger isoform 3 function, and exhibit impaired intestinal absorption; resulting in severe diarrhea, altered salt and water homeostasis, and increased luminal fluid throughout the intestinal tract. Nhe3-null mice have increased PCNA-positive cells in the crypts (indicative of cell proliferation), as well as downregulation of genes involved in xenobiotic metabolism and glutathione metabolism in the intestine (resulting in increased intracellular glutathione levels),
Nhe3-null mice exhibit blunted renal reabsorption in the proximal and distal tubules; but compensatory alterations in filtration rate and/or downstream transport processes ameliorate any severe kidney phenotype. Homozygous null animals have increased levels of kidney renin mRNA and circulating aldosterone, suggesting that they are somewhat volume depleted. Homozygous animals are also acidotic.
Nhe3-null mice have abnormalities of Na⁺/H⁺ exchange and water transport in the epididymis: the efferent ductules/rete testes dilate and the increased fluid volume results in diminished sperm concentration and inability of sperm to fertilize. Nhe3-null mice also exhibit reduced blood pressure.

In addition, Nhe3-deficiency increases survival and decreases the incidence of intestinal obstructions in cystic fibrosis mice (see Stock No. 002196).

Development
A targeting vector was designed to insert a neomycin-resistance cassette into exon 6 of the mouse Na⁺/H⁺ exchanger isoform 3 locus (Nhe3 or Slc9a3) locus. The construct was electroporated into 129-derived embryonic stem (ES) cells. Correctly targeted ES cells were injected into recipient blastocysts. Chimeric males were bred to Black Swiss females to generate the colony. Mutant mice were subsequently backcrossed to FVB/NTac inbred mice for at least ten generations prior to sending to The Jackson Laboratory Repository. Upon arrival, mice were bred with FVB/NJ inbred mice (Stock No. 001800) for at least one generation to establish the colony. During backcrossing, the Y chromosome may not have been fixed to the FVB/N genetic background.

Control Information

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

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.

Slc9a3^tm1Ges/Slc9a3^tm1Ges

        Background Not Specified

• cardiovascular system phenotype
• hypotension   (MGI Ref ID J:70885)
• digestive/alimentary phenotype
• abnormal digestive system physiology
  • pH of the luminal contents was increased in all intestinal sections   (MGI Ref ID J:70885)
• • diarrhea   (MGI Ref ID J:70885)
• abnormal intestine morphology
  • all segments of the intestinal tract were enlarged   (MGI Ref ID J:70885)
• • distended cecum   (MGI Ref ID J:70885)
  • megacolon   (MGI Ref ID J:70885)
• esophageal epithelium hyperplasia   (MGI Ref ID J:70885)
• homeostasis/metabolism phenotype
• abnormal blood pH regulation
  • small, but significant, decreases in pH and hydrocarbonate (HCO₃-)   (MGI Ref ID J:70885)
• abnormal renal water reabsorbtion
  • fluid absorption by proximal renal tubules was reduced by 69%   (MGI Ref ID J:70885)
• increased circulating aldosterone level
  • plasma levels were increased five-fold relative to controls   (MGI Ref ID J:70885)
• renal/urinary system phenotype
• abnormal renal reabsorbtion
  • HCO₃- absorption by proximal renal tubules was reduced by 61%   (MGI Ref ID J:70885)
• • abnormal renal water reabsorbtion
    • fluid absorption by proximal renal tubules was reduced by 69%   (MGI Ref ID J:70885)
• renal tubular acidosis
  • decreases in pH and HCO₃- were consistent with mild proximal tubular acidosis   (MGI Ref ID J:70885)
• endocrine/exocrine gland phenotype
• dilated efferent ductules of testis
  • ductules dilated compared to wild-type, with equal or greater volume compared to Esr1-null mice   (MGI Ref ID J:125658)
• dilated rete testis
  • rete testis dilated compared to wild-type, with equal or greater volume compared to Esr1-null mice   (MGI Ref ID J:125658)
• reproductive system phenotype
• dilated efferent ductules of testis
  • ductules dilated compared to wild-type, with equal or greater volume compared to Esr1-null mice   (MGI Ref ID J:125658)
• dilated rete testis
  • rete testis dilated compared to wild-type, with equal or greater volume compared to Esr1-null mice   (MGI Ref ID J:125658)
• male infertility
  • males are sterile   (MGI Ref ID J:125658)

View Research Applications

Research Applications

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

Cardiovascular Research
Hypotension

Cell Biology Research
Channel and Transporter Defects
      sodium
      sodium/hydrogen

Developmental Biology Research
Internal/Organ Defects
      megacolon
      urogenital
Perinatal Lethality
      Homozygous

Internal/Organ Research
Gastrointestinal Defects
Kidney Defects

Metabolism Research

Neurobiology Research
Channel and Transporter Defects
      sodium
      sodium/hydrogen

Reproductive Biology Research
Developmental Defects Affecting Gonads
      males only
Fertility Defects
      males only

Research Tools
Cell Biology Research
Metabolism Research
Neurobiology Research
Reproductive Biology Research
      male germ cells

Genes & Alleles

Gene & Allele Information provided by MGI

Allele Symbol		Slc9a3tm1Ges
Allele Name		targeted mutation 1, Gary E Shull
Allele Type		Targeted (knock-out)
Common Name(s)		NHE-3 -; Nhe3-; Slc9a3-;
Mutation Made By		Gary Shull,   University of Cincinnati
Gene Symbol and Name		Slc9a3, solute carrier family 9 (sodium/hydrogen exchanger), member 3
Chromosome		13
Gene Common Name(s)		9030624O13Rik; AI930210; NHE-3; NHE3; RIKEN cDNA 9030624O13 gene; expressed sequence AI930210;
Molecular Note		The gene was disrupted by insertion of a neomycin resistance cassette into exon 6. Northern blot analysis of kidney and intestinal RNA detected a truncated mutant transcript lacking codons 320-821. The residues endcoded by the deleted sequences are required for Na+/H+ exhange. [MGI Ref ID J:70885]

Genotyping

Genotyping Information

Helpful Links

Genotyping resources and troubleshooting

References

References provided by MGI

Selected Reference(s)

Bradford EM; Sartor MA; Gawenis LR; Clarke LL; Shull GE. 2009. Reduced NHE3-mediated Na+ absorption increases survival and decreases the incidence of intestinal obstructions in cystic fibrosis mice. Am J Physiol Gastrointest Liver Physiol 296(4):G886-98. [PubMed: 19164484]  [MGI Ref ID J:149709]

Lorenz JN; Schultheis PJ; Traynor T; Shull GE; Schnermann J. 1999. Micropuncture analysis of single-nephron function in NHE3-deficient mice. Am J Physiol 277(3 Pt 2):F447-53. [PubMed: 10484528]  [MGI Ref ID J:160211]

Mennone A; Biemesderfer D; Negoianu D; Yang CL; Abbiati T; Schultheis PJ; Shull GE; Aronson PS; Boyer JL. 2001. Role of sodium/hydrogen exchanger isoform NHE3 in fluid secretion and absorption in mouse and rat cholangiocytes. Am J Physiol Gastrointest Liver Physiol 280(2):G247-54. [PubMed: 11208547]  [MGI Ref ID J:160210]

Schultheis PJ; Clarke LL; Meneton P; Harline M; Boivin GP; Stemmermann G ; Duffy JJ ; Doetschman T ; Miller ML ; Shull GE. 1998. Targeted disruption of the murine Na+/H+ exchanger isoform 2 gene causes reduced viability of gastric parietal cells and loss of net acid secretion. J Clin Invest 101(6):1243-53. [PubMed: 9502765]  [MGI Ref ID J:46545]

Schultheis PJ; Clarke LL; Meneton P; Miller ML; Soleimani M; Gawenis LR; Riddle TM; Duffy JJ; Doetschman T; Wang T; Giebisch G; Aronson PS; Lorenz JN; Shull GE. 1998. Renal and intestinal absorptive defects in mice lacking the NHE3 Na+/H+ exchanger. Nat Genet 19(3):282-5. [PubMed: 9662405]  [MGI Ref ID J:70885]

Additional References

Slc9a3^tm1Ges related

Amlal H; Ledoussal C; Sheriff S; Shull GE; Soleimani M. 2003. Downregulation of renal AQP2 water channel and NKCC2 in mice lacking the apical Na+-H+ exchanger NHE3. J Physiol 553(Pt 2):511-22. [PubMed: 14500765]  [MGI Ref ID J:105423]

Bailey MA; Giebisch G; Abbiati T; Aronson PS; Gawenis LR; Shull GE; Wang T. 2004. NHE2-mediated bicarbonate reabsorption in the distal tubule of NHE3 null mice. J Physiol 561(Pt 3):765-75. [PubMed: 15604231]  [MGI Ref ID J:105509]

Beck FX; Neuhofer W; Dorge A; Giebisch G; Wang T. 2003. Intracellular Na concentration and Rb uptake in proximal convoluted tubule cells and abundance of Na/K-ATPase alpha1-subunit in NHE3-/- mice. Pflugers Arch 446(1):100-5. [PubMed: 12690468]  [MGI Ref ID J:106176]

Brooks HL; Sorensen AM; Terris J; Schultheis PJ; Lorenz JN; Shull GE; Knepper MA. 2001. Profiling of renal tubule Na+ transporter abundances in NHE3 and NCC null mice using targeted proteomics. J Physiol 530(Pt 3):359-66. [PubMed: 11158268]  [MGI Ref ID J:106313]

Brown DA; Melvin JE; Yule DI. 2003. Critical role for NHE1 in intracellular pH regulation in pancreatic acinar cells. Am J Physiol Gastrointest Liver Physiol 285(5):G804-12. [PubMed: 12842825]  [MGI Ref ID J:108051]

Catalan MA; Nakamoto T; Gonzalez-Begne M; Camden JM; Wall SM; Clarke LL; Melvin JE. 2010. Cftr and ENaC ion channels mediate NaCl absorption in the mouse submandibular gland. J Physiol 588(Pt 4):713-24. [PubMed: 20026617]  [MGI Ref ID J:176780]

Chen M; Sultan A; Cinar A; Yeruva S; Riederer B; Singh AK; Li J; Bonhagen J; Chen G; Yun C; Donowitz M; Hogema B; de Jonge H; Seidler U. 2010. Loss of PDZ-adaptor protein NHERF2 affects membrane localization and cGMP- and [Ca2+]- but not cAMP-dependent regulation of Na+/H+ exchanger 3 in murine intestine. J Physiol 588(Pt 24):5049-63. [PubMed: 20962002]  [MGI Ref ID J:179543]

Choi JY; Shah M; Lee MG; Schultheis PJ; Shull GE; Muallem S; Baum M. 2000. Novel amiloride-sensitive sodium-dependent proton secretion in the mouse proximal convoluted tubule J Clin Invest 105(8):1141-6. [PubMed: 10772659]  [MGI Ref ID J:61670]

Clayburgh DR; Musch MW; Leitges M; Fu YX; Turner JR. 2006. Coordinated epithelial NHE3 inhibition and barrier dysfunction are required for TNF-mediated diarrhea in vivo. J Clin Invest 116(10):2682-94. [PubMed: 17016558]  [MGI Ref ID J:114497]

Evans RL; Bell SM; Schultheis PJ; Shull GE; Melvin JE. 1999. Targeted disruption of the Nhe1 gene prevents muscarinic agonist-induced up-regulation of Na(+)/H(+) exchange in mouse parotid acinar cells. J Biol Chem 274(41):29025-30. [PubMed: 10506152]  [MGI Ref ID J:111073]

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]

Gawenis LR; Stien X; Shull GE; Schultheis PJ; Woo AL; Walker NM; Clarke LL. 2002. Intestinal NaCl transport in NHE2 and NHE3 knockout mice. Am J Physiol Gastrointest Liver Physiol 282(5):G776-84. [PubMed: 11960774]  [MGI Ref ID J:108284]

Gekle M; Volker K; Mildenberger S; Freudinger R; Shull GE; Wiemann M. 2004. NHE3 Na+/H+ exchanger supports proximal tubular protein reabsorption in vivo. Am J Physiol Renal Physiol 287(3):F469-73. [PubMed: 15113744]  [MGI Ref ID J:95425]

Guan Y; Dong J; Tackett L; Meyer JW; Shull GE; Montrose MH. 2006. NHE2 is the main apical NHE in mouse colonic crypts but an alternative Na+-dependent acid extrusion mechanism is upregulated in NHE2-null mice. Am J Physiol Gastrointest Liver Physiol 291(4):G689-99. [PubMed: 16690903]  [MGI Ref ID J:116869]

Larmonier CB; Laubitz D; Thurston RD; Bucknam AL; Hill FM; Midura-Kiela M; Ramalingam R; Kiela PR; Ghishan FK. 2011. NHE3 modulates the severity of colitis in IL-10-deficient mice. Am J Physiol Gastrointest Liver Physiol 300(6):G998-G1009. [PubMed: 21415416]  [MGI Ref ID J:174245]

Laubitz D; Larmonier CB; Bai A; Midura-Kiela MT; Lipko MA; Thurston RD; Kiela PR; Ghishan FK. 2008. Colonic gene expression profile in NHE3-deficient mice: evidence for spontaneous distal colitis. Am J Physiol Gastrointest Liver Physiol 295(1):G63-G77. [PubMed: 18467500]  [MGI Ref ID J:137547]

Ledoussal C; Lorenz JN; Nieman ML; Soleimani M; Schultheis PJ; Shull GE. 2001. Renal salt wasting in mice lacking NHE3 Na+/H+ exchanger but not in mice lacking NHE2. Am J Physiol Renal Physiol 281(4):F718-27. [PubMed: 11553519]  [MGI Ref ID J:72094]

Ledoussal C; Woo AL; Miller ML; Shull GE. 2001. Loss of the NHE2 Na(+)/H(+) exchanger has no apparent effect on diarrheal state of NHE3-deficient mice. Am J Physiol Gastrointest Liver Physiol 281(6):G1385-96. [PubMed: 11705743]  [MGI Ref ID J:108636]

Lee MG; Ahn W; Choi JY; Luo X; Seo JT; Schultheis PJ; Shull GE; Kim KH; Muallem S. 2000. Na(+)-dependent transporters mediate HCO(3)(-) salvage across the luminal membrane of the main pancreatic duct. J Clin Invest 105(11):1651-8. [PubMed: 10841524]  [MGI Ref ID J:62759]

Luo X; Choi JY; Ko SB; Pushkin A; Kurtz I; Ahn W; Lee MG; Muallem S. 2001. HCO3- salvage mechanisms in the submandibular gland acinar and duct cells. J Biol Chem 276(13):9808-16. [PubMed: 11139574]  [MGI Ref ID J:68657]

Nakamura S; Amlal H; Schultheis PJ; Galla JH; Shull GE; Soleimani M. 1999. HCO-3 reabsorption in renal collecting duct of NHE-3-deficient mouse: a compensatory response. Am J Physiol 276(6 Pt 2):F914-21. [PubMed: 10362780]  [MGI Ref ID J:111450]

Noonan WT; Woo AL; Nieman ML; Prasad V; Schultheis PJ; Shull GE; Lorenz JN. 2005. Blood pressure maintenance in NHE3-deficient mice with transgenic expression of NHE3 in small intestine. Am J Physiol Regul Integr Comp Physiol 288(3):R685-91. [PubMed: 15550620]  [MGI Ref ID J:96652]

Pan W; Borovac J; Spicer Z; Hoenderop JG; Bindels RJ; Shull GE; Doschak MR; Cordat E; Alexander RT. 2012. The epithelial sodium/proton exchanger, NHE3, is necessary for renal and intestinal calcium (re)absorption. Am J Physiol Renal Physiol 302(8):F943-56. [PubMed: 21937605]  [MGI Ref ID J:183341]

Park K; Evans RL; Watson GE; Nehrke K; Richardson L; Bell SM; Schultheis PJ; Hand AR; Shull GE; Melvin JE. 2001. Defective fluid secretion and NaCl absorption in the parotid glands of Na+/H+ exchanger-deficient mice. J Biol Chem 276(29):27042-50. [PubMed: 11358967]  [MGI Ref ID J:70551]

Singh AK; Riederer B; Chen M; Xiao F; Krabbenhoft A; Engelhardt R; Nylander O; Soleimani M; Seidler U. 2010. The switch of intestinal Slc26 exchangers from anion absorptive to HCOFormula secretory mode is dependent on CFTR anion channel function. Am J Physiol Cell Physiol 298(5):C1057-65. [PubMed: 20164375]  [MGI Ref ID J:159251]

Walker NM; Simpson JE; Yen PF; Gill RK; Rigsby EV; Brazill JM; Dudeja PK; Schweinfest CW; Clarke LL. 2008. Down-regulated in adenoma Cl/HCO3 exchanger couples with Na/H exchanger 3 for NaCl absorption in murine small intestine. Gastroenterology 135(5):1645-1653.e3. [PubMed: 18930060]  [MGI Ref ID J:145623]

Wang T; Yang CL; Abbiati T; Schultheis PJ; Shull GE; Giebisch G ; Aronson PS. 1999. Mechanism of proximal tubule bicarbonate absorption in NHE3 null mice. Am J Physiol 277(2 Pt 2):F298-302. [PubMed: 10444585]  [MGI Ref ID J:57396]

Wang T; Yang CL; Abbiati T; Shull GE; Giebisch G; Aronson PS. 2001. Essential role of NHE3 in facilitating formate-dependent NaCl absorption in the proximal tubule. Am J Physiol Renal Physiol 281(2):F288-92. [PubMed: 11457720]  [MGI Ref ID J:114406]

Woo AL; Gildea LA; Tack LM; Miller ML; Spicer Z; Millhorn DE; Finkelman FD; Hassett DJ; Shull GE. 2002. In vivo evidence for interferon-gamma-mediated homeostatic mechanisms in small intestine of the NHE3 Na+/H+ exchanger knockout model of congenital diarrhea. J Biol Chem 277(50):49036-46. [PubMed: 12370192]  [MGI Ref ID J:80707]

Woo AL; Noonan WT; Schultheis PJ; Neumann JC; Manning PA; Lorenz JN; Shull GE. 2003. Renal function in NHE3-deficient mice with transgenic rescue of small intestinal absorptive defect. Am J Physiol Renal Physiol 284(6):F1190-8. [PubMed: 12582007]  [MGI Ref ID J:83902]

Xu H; Li J; Chen R; Zhang B; Wang C; King N; Chen H; Ghishan FK. 2011. NHE2X3 DKO mice exhibit gender-specific NHE8 compensation. Am J Physiol Gastrointest Liver Physiol 300(4):G647-53. [PubMed: 21252044]  [MGI Ref ID J:171150]

Zhou Q; Clarke L; Nie R; Carnes K; Lai LW; Lien YH; Verkman A; Lubahn D; Fisher JS; Katzenellenbogen BS; Hess RA. 2001. Estrogen action and male fertility: roles of the sodium/hydrogen exchanger-3 and fluid reabsorption in reproductive tract function. Proc Natl Acad Sci U S A 98(24):14132-7. [PubMed: 11698654]  [MGI Ref ID J:125658]

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 & Husbandry	When maintaining a live colony, heterozygous mice may be bred together, to wildtype siblings, or to FVB/NJ inbred mice (Stock No. 001800). When maintained as congenic on the FVB/N genetic background, homozygous mice exhibit a high mortality rate beginning just after weaning, with ~30% surviving to adulthood. Homozygous females are fertile, but homozygous males are infertile.

Pricing and Purchasing

Pricing, Supply Level & Notes, Controls

Control Information

	Control
	Wild-type from the colony
	001800 FVB/NJ
Considerations for Choosing Controls
Control Pricing Information for Genetically Engineered Mutant Strains.

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Terms are granted by individual review and stated on the customer invoice(s) and account statement. These transactions are payable in U.S. currency within the granted terms. Payment for services, products, shipping containers, and shipping costs that are rendered are expected within the payment terms indicated on the invoice or stated by contract. Invoices and account balances in arrears of stated terms may result in The Jackson Laboratory pursuing collection activities including but not limited to outside agencies and court filings.

See Terms of Use tab for General Terms and Conditions

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.

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