These Nhe3 mutant mice harbor a targeted mutation of the Na+/H+ exchanger isoform 3 locus (Nhe3 or Slc9a3) that abolishes endogenous gene expression. Nhe3 mutant mice may be useful in studying intestinal secretion/absorption in maintaining luminal fluid homeostasis, fluid reabsorption in other organ systems (including kidney and efferent ductules of the male reproductive tract), and neuronal control of respiration.
Gary E Shull, University of CincinnatiRead More +
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).
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.
|Allele Name||targeted mutation 1, Gary E Shull|
|Allele Type||Targeted (Null/Knockout)|
|Allele Synonym(s)||NHE-3 -; Nhe3-; Slc9a3-|
|Gene Symbol and Name||Slc9a3, solute carrier family 9 (sodium/hydrogen exchanger), member 3|
|Gene Synonym(s)||9030624O13Rik; 9030624O13Rik; AI930210; DIAR8; NHE-3; NHE3; Nhe3; RIKEN cDNA 9030624O13 gene; expressed sequence AI930210|
|Strain of Origin||Not Specified|
|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.|
|Mutations Made By|| |
Gary Shull, University of Cincinnati
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.
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