Description

Strain Information

Former Names B6.129P2(Cg)-Slc17a8tm1Edw/J    (Changed: 28-JUN-12 ) Type Mutant Stock; Targeted Mutation; Additional information on Genetically Engineered and Mutant Mice. Visit our online Nomenclature tutorial. Mating System Heterozygote x Heterozygote         (Female x Male)   10-MAY-12 Species laboratory mouse   Donating Investigator Robert Edwards,   UCSF

Description
An enhanced green fluorescent protein (EGFP) replaces most of exon 2 of the solute carrier family 17, member 8 (Slc17a8 or Vglut3) gene in these mice. Gene function is abolished. EGFP signal is not detected. Homozygotes are viable, fertile, and normal in size. VGLUT3 is a vesicular glutamate transporter that mediates synaptic transmission by transporting the neurotransmitter, glutamate, into secretory vesicles. In wildtype mice, VGLUT3 is expressed by inner hair cells of the cochlea, by serotonergic neurons, cholinergic neurons, a particular subset of primary sensory afferents (low-threshold mechanoreceptors), a subset of GABAergic interneurons, and a variety of other cell populations, some not known to use glutamate as a transmitter. These VGLUT3 deficient mice are deaf and exhibit epileptic seizures with little change in motor behavior.

Development
A targeting vector was designed to replace most of exon 2 encoding the solute carrier family 17, member 8 (Slc17a8 or Vglut3) gene with an enhanced green fluorescent protein (EGFP) followed by a polyadenylation signal and a floxed-neomycin resistance (neo) cassette. The construct was electroporated into 129P2/Ola-derived embryonic stem (ES) cells. Correctly targeted ES cells were injected into blastocysts and the resulting chimeric males were bred to C57BL/6 females. Heterozygous offspring were subsequently bred to mice expressing ACTB-cre to delete the neo cassette. The donating investigator reported that these mice were backcrossed at least 10 generations to C57BL/6 background (see SNP note below). Upon arrival at The Jackson Laboratory, mice were bred to C57BL/6J (Stock No. 000664) for at least one generation to establish the colony.

A 32 SNP (single nucleotide polymorphism) panel analysis, with 27 markers covering all 19 chromosomes and the X chromosome, as well as 5 markers that distinguish between the C57BL/6J and C57BL/6N substrains, was performed on the rederived living colony at The Jackson Laboratory Repository. 6 of the 27 markers throughout the genome were segregating between B6J and 129, suggesting an incomplete backcross.

Control Information

	Control
	Wild-type from the colony
	000664 C57BL/6J	(approximate)
Considerations for Choosing Controls

Related Strains

Strains carrying other alleles of Slc17a8

018148	STOCK Tg(Slc17a8-EGFP)1Edw/SealJ
018147	STOCK Tg(Slc17a8-icre)1Edw/SealJ

View Strains carrying other alleles of Slc17a8     (2 strains)

Phenotype

Phenotype Information

View Related Disease (OMIM) Terms

Related Disease (OMIM) Terms provided by MGI

- Potential model based on gene homology relationships. Phenotypic similarity to the human disease has not been tested. Deafness, Autosomal Dominant 25; DFNA25   (SLC17A8)

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.

Slc17a8^tm1Edw/Slc17a8⁺

        involves: 129P2/OlaHsd * C57BL/6

• nervous system phenotype
• abnormal brain wave pattern
  • mice exhibit interictal epileptiform abnormalities but no detectable electrographic seizure   (MGI Ref ID J:132704)

Slc17a8^tm1Edw/Slc17a8^tm1Edw

        involves: 129P2/OlaHsd * C57BL/6

• nervous system phenotype
• abnormal brain wave pattern
  • mice exhibit frequent interictal spike discharges   (MGI Ref ID J:132704)
• abnormal inner hair cell synaptic ribbon morphology
  • 26 of 31 inner cell synapses exhibit abnormally thin, elongated ribbons   (MGI Ref ID J:132704)
• cochlear ganglion degeneration
  • mice exhibit progressive neuron loss at all levels of the cochlea that is apparent by P10   (MGI Ref ID J:132704)
• decreased synaptic glutamate release
  • mice do not exhibit no synaptic response in the inner hair cell afferent terminals even when depolarized by elevated potassium   (MGI Ref ID J:132704)
• nonconvulsive seizures
  • mice exhibit intermittent spontaneous cortical seizures lasting up to 2 minutes   (MGI Ref ID J:132704)
  • however, mice do not display any behavioral abnormalities   (MGI Ref ID J:132704)
• hearing/vestibular/ear phenotype
• abnormal inner hair cell synaptic ribbon morphology
  • 26 of 31 inner cell synapses exhibit abnormally thin, elongated ribbons   (MGI Ref ID J:132704)
• deafness   (MGI Ref ID J:132704)
• increased or absent threshold for auditory brainstem response   (MGI Ref ID J:132704)
• sensorineural hearing loss   (MGI Ref ID J:132704)
• behavior/neurological phenotype
• absent startle reflex
  • mice do not startle to a loud clap   (MGI Ref ID J:132704)
  • however, motor and vestibular functions are normal   (MGI Ref ID J:132704)
• nonconvulsive seizures
  • mice exhibit intermittent spontaneous cortical seizures lasting up to 2 minutes   (MGI Ref ID J:132704)
  • however, mice do not display any behavioral abnormalities   (MGI Ref ID J:132704)

View Research Applications

Research Applications

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

Developmental Biology Research
Neurodevelopmental Defects

Neurobiology Research
Channel and Transporter Defects
Epilepsy
Hearing Defects
Neurotransmitter Receptor and Synaptic Vesicle Defects

Genes & Alleles

Gene & Allele Information provided by MGI

Allele Symbol		Slc17a8tm1Edw
Allele Name		targeted mutation 1, Robert H Edwards
Allele Type		Targeted (knock-out)
Common Name(s)		VGLUT3-;
Mutation Made By		Robert Edwards,   UCSF
Strain of Origin		129P2/OlaHsd
Gene Symbol and Name		Slc17a8, solute carrier family 17 (sodium-dependent inorganic phosphate cotransporter), member 8
Chromosome		10
Gene Common Name(s)		BC042593; DFNA25; VGLUT3; cDNA sequence BC042593;
Molecular Note		Most of exon 2 was replaced with an EGFP cassette, with a stop codon and poly-adenylation signal, and floxed neo cassette. Germ-line, cre-mediated recombination was used to remove the neo cassette. The absence of protein product was confirmed by western blot analysis on brain extracts. However, no EGFP signal was detected. [MGI Ref ID J:132704]

Genotyping

Genotyping Information

Genotyping Protocols

Slc17a8^tm1Edw, Separated PCR

Helpful Links

Genotyping resources and troubleshooting

References

References provided by MGI

Selected Reference(s)

Seal RP; Akil O; Yi E; Weber CM; Grant L; Yoo J; Clause A; Kandler K; Noebels JL; Glowatzki E; Lustig LR; Edwards RH. 2008. Sensorineural deafness and seizures in mice lacking vesicular glutamate transporter 3. Neuron 57(2):263-75. [PubMed: 18215623]  [MGI Ref ID J:132704]

Additional References

Slc17a8^tm1Edw related

Akil O; Seal RP; Burke K; Wang C; Alemi A; During M; Edwards RH; Lustig LR. 2012. Restoration of hearing in the VGLUT3 knockout mouse using virally mediated gene therapy. Neuron 75(2):283-93. [PubMed: 22841313]  [MGI Ref ID J:188349]

Blankenship AG; Ford KJ; Johnson J; Seal RP; Edwards RH; Copenhagen DR; Feller MB. 2009. Synaptic and extrasynaptic factors governing glutamatergic retinal waves. Neuron 62(2):230-41. [PubMed: 19409268]  [MGI Ref ID J:157363]

Noh J; Seal RP; Garver JA; Edwards RH; Kandler K. 2010. Glutamate co-release at GABA/glycinergic synapses is crucial for the refinement of an inhibitory map. Nat Neurosci 13(2):232-8. [PubMed: 20081852]  [MGI Ref ID J:156675]

Seal RP; Wang X; Guan Y; Raja SN; Woodbury CJ; Basbaum AI; Edwards RH. 2009. Injury-induced mechanical hypersensitivity requires C-low threshold mechanoreceptors. Nature 462(7273):651-5. [PubMed: 19915548]  [MGI Ref ID J:155581]

Shields SD; Ahn HS; Yang Y; Han C; Seal RP; Wood JN; Waxman SG; Dib-Hajj SD. 2012. Nav1.8 expression is not restricted to nociceptors in mouse peripheral nervous system. Pain 153(10):2017-30. [PubMed: 22703890]  [MGI Ref ID J:190164]

Health & husbandry

Health & Colony Maintenance Information

Animal Health Reports

Room Number           AX18

Colony Maintenance

Breeding & Husbandry	When maintaining a live colony, homozygous mice may be bred together.
Mating System	Heterozygote x Heterozygote         (Female x Male)   10-MAY-12

Pricing and Purchasing

Pricing, Supply Level & Notes, Controls

Control Information

	Control
	Wild-type from the colony
	000664 C57BL/6J	(approximate)
Considerations for Choosing Controls
Control Pricing Information for Genetically Engineered Mutant Strains.

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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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