Description

Strain Information

Type Mutant Strain; Targeted Mutation; Additional information on Genetically Engineered and Mutant Mice. Visit our online Nomenclature tutorial. Mating System Wild-type x Heterozygote         (Female x Male)   05-FEB-13 Mating System Heterozygote x Wild-type         (Female x Male)   05-FEB-13 Species laboratory mouse Generation N1 (11-FEB-13) Generation Definitions   Donating Investigator Joseph D Buxbaum,   Mount Sinai School of Medicine

Description
These mutant mice harbor a deletion of the SH3/ankyrin domain gene 3 ankyrin repeat domains (exons 4-9). This deletion prevents full-length Shank3 expression; Shank3 mRNA/protein is absent in homozygous postsynaptic density (PSD) fractions, and reduced 50% in heterozygous PSD fractions. Heterozygous mice are viable and fertile with no observed gross brain structure defects or seizures. Heterozygous mice exhibit reduced basal neurotransmission. Heterozygous males display less social sniffing and emit fewer ultrasonic vocalizations during interactions with estrus female mice. Following theta-burst pairing (coincident pre- and postsynaptic stimulation), heterozygous mice have impaired long-term potentiation and altered spine remodeling. Homozygous mice are viable with subtle motor abnormalities. The complete phenotype of homozygous mice is not yet characterized to date (April 2012).

Development
A targeting vector was designed to insert a loxP site upstream of exon 4, and an frt-flanked selection (neo) cassette followed by a second loxP site all downstream of exon 9 of the targeted gene. The construct was electroporated into B6.Cg-Thy1^a-derived Bruce4 embryonic stem (ES) cells. Correctly targeted ES cells were injected into recipient blastocysts. Chimeric males were bred with C57BL/6NTac females to establish the colony. Next, mutant mice were bred with FLP-expressing mice (undisclosed genetic background) to remove the frt-flanked PGK-neo cassette. The resulting Shank3^{flox ex4-9} mice were subsequently bred to C57BL/6-congenic mice expressing Cre recombinase in embryonic tissues (CMV-Cre; see Stock No. 006054). The resulting mice with pan deletion of the Shank3 ankyrin repeat domains were obtained. These mice were then bred to C57BL/6NTac for two-to-three generations (and the Cre recombinase gene was removed) prior to sending to The Jackson Laboratory Repository. Upon arrival, mice were bred to C57BL/6J inbred mice (Stock No. 000664) for at least one generation to establish The Jackson Laboratory Repository colony. Of note, while backcrossing the donating investigator did not assay their colony at the Thy1 locus. As such, these mice may be segregating for the NZB-derived Thy1^a allele (from Bruce4 ES cells) or the C57BL/6-derived Thy1^b allele.

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. While the 27 markers throughout the genome suggested a C57BL/6 genetic background, all 5 markers that determine C57BL/6J from C57BL/6N were found to be segregating. These data suggest the mice sent to The Jackson Laboratory Repository were on a mixed C57BL/6J ; C57BL/6N genetic background.

Control Information

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

Related Strains

Strains carrying other alleles of Shank3

017889	B6(Cg)-Shank3tm1.1Bux/J
017688	B6.129-Shank3tm2Gfng/J
017442	B6.129S7-Shank3tm1Yhj/J
018398	STOCK Shank3tm1.1Pfw/J

View Strains carrying other alleles of Shank3     (4 strains)

Phenotype

Phenotype Information

View Related Disease (OMIM) Terms

Related Disease (OMIM) Terms provided by MGI

- Model with phenotypic similarity to human disease where etiologies are distinct. Human genes are associated with this disease. Orthologs of these genes do not appear in the mouse genotype(s).

Autism

- Potential model based on gene homology relationships. Phenotypic similarity to the human disease has not been tested. Phelan-Mcdermid Syndrome   (SHANK3) Schizophrenia 15; SCZD15   (SHANK3)

View Mammalian Phenotype Terms

Mammalian Phenotype Terms provided by MGI

      assigned by genotype

Shank3^tm1.2Bux/Shank3⁺

        C57BL/6-Shank3^tm1.2Bux

• nervous system phenotype
• abnormal neuron physiology
  • spine enlargement accompanying long term potentiation is impaired   (MGI Ref ID J:175320)
• abnormal synaptic transmission
  • decrease in the paired pulse ratio   (MGI Ref ID J:175320)
• • abnormal excitatory postsynaptic potential
    • reduction in the I/O curves of field excitatory postsynaptic potentials in hippocampal slices from 3-4 week old mice   (MGI Ref ID J:175320)
    • decrease in AMPA receptor mediated field potentials   (MGI Ref ID J:175320)
  • abnormal miniature excitatory postsynaptic currents
    • significantly higher frequency of miniature excitatory postsynaptic currents   (MGI Ref ID J:175320)
  • reduced long term potentiation
    • initial expression of LTP is normal but maintenance is impaired   (MGI Ref ID J:175320)
• behavior/neurological phenotype
• abnormal social investigation
  • total social sniffing by the males is lower   (MGI Ref ID J:175320)
  • however, no defect in olfactory abilities are detected   (MGI Ref ID J:175320)
• abnormal vocalization
  • fewer ultrasonic vocalizations emitted during male-female social interactions session   (MGI Ref ID J:175320)

View Research Applications

Research Applications

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

Cell Biology Research
Channel and Transporter Defects

Neurobiology Research
Behavioral and Learning Defects
Channel and Transporter Defects
      calcium: glutamate receptor
Cre-lox System
      loxP-flanked Sequences
Neurodevelopmental Defects
      Autism
Neurotransmitter Receptor and Synaptic Vesicle Defects
Receptor Defects
      glutamate receptor: NMDA

Research Tools
Cre-lox System
      loxP-flanked Sequences
Developmental Biology Research
      Cre-lox System
Genetics Research
      Mutagenesis and Transgenesis: Cre-lox System
      Tissue/Cell Markers: Cre-lox System

Genes & Alleles

Gene & Allele Information provided by MGI

Allele Symbol		Shank3tm1.2Bux
Allele Name		targeted mutation 1.2, Joseph D Buxbaum
Allele Type		Targeted (knock-out)
Mutation Made By		Joseph Buxbaum,   Mount Sinai School of Medicine
Strain of Origin		B6.Cg-Thy1
Gene Symbol and Name		Shank3, SH3/ankyrin domain gene 3
Chromosome		15
Gene Common Name(s)		AI841104; ProSAP2; expressed sequence AI841104;
Molecular Note		A loxP site was inserted upstream of exon 4 and an FRT flanked neo cassette and second loxP site were inserted downstream of exon 9 via homologous recombination. Flp mediated recombination removed the neo cassette. Cre mediated recombination removed exons 4 - 9. Quantitative PCR and immunoblot analysis confirmed the absence of mRNA and protein expression in homozygous mice. [MGI Ref ID J:175320]

Genotyping

Genotyping Information

Genotyping Protocols

Shank3^tm1.2Bux ,

Separated MCA

Tg(ACTFLPe), High Resolution Melting
Shank3^tm1.2Bux, Separated PCR

Helpful Links

Genotyping resources and troubleshooting

References

References provided by MGI

Selected Reference(s)

Bozdagi O; Sakurai T; Papapetrou D; Wang X; Dickstein DL; Takahashi N; Kajiwara Y; Yang M; Katz AM; Scattoni ML; Harris MJ; Saxena R; Silverman JL; Crawley JN; Zhou Q; Hof PR; Buxbaum JD. 2010. Haploinsufficiency of the autism-associated Shank3 gene leads to deficits in synaptic function, social interaction, and social communication. Mol Autism 1(1):15. [PubMed: 21167025]  [MGI Ref ID J:175320]

Additional References

Shank3^tm1.2Bux related

Yang M; Bozdagi O; Scattoni ML; Wohr M; Roullet FI; Katz AM; Abrams DN; Kalikhman D; Simon H; Woldeyohannes L; Zhang JY; Harris MJ; Saxena R; Silverman JL; Buxbaum JD; Crawley JN. 2012. Reduced excitatory neurotransmission and mild autism-relevant phenotypes in adolescent Shank3 null mutant mice. J Neurosci 32(19):6525-41. [PubMed: 22573675]  [MGI Ref ID J:184855]

Health & husbandry

Health & Colony Maintenance Information

Animal Health Reports

Room Number           AX18

Colony Maintenance

Breeding & Husbandry	Heterozygous males display less social sniffing and emit fewer ultrasonic vocalizations during interactions with estrus female mice. Therefore when maintaining a live colony, heterozygous females may be bred with wildtype males from the colony or with C57BL/6J inbred males (Stock No. 000664).
Mating System	Wild-type x Heterozygote         (Female x Male)   05-FEB-13
	Heterozygote x Wild-type         (Female x Male)   05-FEB-13
Diet Information	LabDiet® 5K52/5K67

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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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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