Description

Strain Information

Former Names B6.129S6(Cg)-Shank3tm1.1Pfw/J    (Changed: 20-DEC-12 ) B6.Cg-Shank3tm1.1Pfw/J    (Changed: 10-MAY-12 ) Type Congenic; Mutant Stock; Targeted Mutation; Additional information on Genetically Engineered and Mutant Mice. Visit our online Nomenclature tutorial. Additional information on Congenic nomenclature. Mating System +/+ sibling x Heterozygote         (Female x Male)   07-AUG-12 Species laboratory mouse Generation N6pN1+ (07-AUG-12) Generation Definitions   Donating Investigator Paul Worley,   Johns Hopkins University School of Medic

Description
These Shank3(+/ΔC) mutant mice lack exon 21 of the SH3/ankyrin domain gene 3 (Shank3) gene. The removal of exon 21 causes a frameshift which results in the production of SHANK3 protein lacking the entire C-terminal region, including the Homer-binding site in the sterile alpha motif (SAM) domain. SHANK3 is a synaptic scaffolding protein expressed in the postsynaptic density (PSD) of excitatory synapses. SHANK3 mutations have been identified in cases of intellectual disability such as autism spectrum disorder (ASD), Phelan-McDermid syndrome, and schizophrenia. Truncated SHANK3 protein associates with wildtype protein resulting in a 75% reduction in wildtype SHANK3 in cortical cultures, and 90% reduction in synaptic cultures. These Shank3(+/ΔC) mice exhibit behavioral deficits suggestive of autism, including aberrant social interactions leading to aggressive behaviors. These mice also have reduced NMDA receptor function in hippocampal neurons resulting in the reductions in long term potential and depression. Shank3(+/ΔC) mice display normal learning and memory, and show no alterations in postsynaptic density proteins, spine morphology, or synapse number. Mice that are heterozygous for this allele are viable and fertile. The donating investigator has reported some fertility issues when maintaining a homozygous colony.

Development
A targeting vector was designed to insert a loxP site upstream of exon 21 followed by a frt-flanked neomycin resistance (neo) cassette, and a second loxP site downstream of exon 21 of the SH3/ankyrin domain gene 3 (Shank3) gene. The construct was electroporated into 129S6/SvEvTac embryonic stem (ES) cells. Correctly targeted ES cells were injected into C57BL/6J blastocysts and resulting chimeric mice were bred to C57BL/6J mice. The resulting offspring, were bred with mice expressing actin-cre to delete the neo cassette and exon 21, and progeny were crossed to remove the Cre-expressing transgene. The donating investigator reported that the resulting Shank3(ΔC) mice were bred to C57BL/6J mice for at least 5 generations (see SNP note below). Upon arrival, mice were bred to C57BL/6J inbred mice (Stock No. 000664) 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. 18 of the 27 markers throughout the genome were found to be segregating for 129 and B6. Also, 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 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
017890	B6(Cg)-Shank3tm1.2Bux/J
017688	B6.129-Shank3tm2Gfng/J
017442	B6.129S7-Shank3tm1Yhj/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. Chromosome 22q13.3 Deletion Syndrome   (SHANK3) Schizophrenia 15; SCZD15   (SHANK3)

View Mammalian Phenotype Terms

Mammalian Phenotype Terms provided by MGI

      assigned by genotype

Shank3^tm1.1Pfw/Shank3⁺

        B6.129S6-Shank3^tm1.1Pfw

• behavior/neurological phenotype
• *normal* behavior/neurological phenotype
  • mice exhibit normal short-term spatial recognition, spatial working memory, context and cue-related fear memory and extinction, anxiety levels, and learning of motor skills   (MGI Ref ID J:173397)
• • abnormal social/conspecific interaction
    • mice exhibit reduced social investigation modulated by episodes of aggression compared with wild-type mice   (MGI Ref ID J:173397)
  • • abnormal social investigation
      • mice exhibit reduced social investigation modulated by episodes of aggression compared with wild-type mice   (MGI Ref ID J:173397)
      • male mice spend more time investigating an enclosed male stimulus compared with wild-type mice   (MGI Ref ID J:173397)
      • male mice exhibit increased latency to approach a sexually receptive enclosed female mouse compared with wild-type mice   (MGI Ref ID J:173397)
      • however, mice exhibit normal social recognition memory   (MGI Ref ID J:173397)
    • increased aggression towards mice
      • mice exhibit increased aggression towards a novel stimulus mouse and in a resident-intruder tests compared with wild-type mice   (MGI Ref ID J:173397)
  • abnormal vocalization
    • male mice exhibit latency to first ultrasound call in the presence of a female mice compared with wild-type mice   (MGI Ref ID J:173397)
  • decreased startle reflex
    • mice exhibit lower amplitudes and longer latencies of startle response compared with wild-type mice   (MGI Ref ID J:173397)
  • induced hyperactivity
    • in dizocilpine- or amphetamine-treated mice   (MGI Ref ID J:173397)
    • however, mice do not exhibit novelty-induced hyperactivity   (MGI Ref ID J:173397)
• nervous system phenotype
• abnormal glutamate-mediated receptor currents
  • the ratio of NMDA to AMPA-dependent response in the cortex is reduced compared to in wild-type mice   (MGI Ref ID J:173397)
  • however, AMPAR-mediated miniature excitatory postsynaptic current amplitude and frequency are normal   (MGI Ref ID J:173397)
• • reduced NMDA-mediated synaptic currents   (MGI Ref ID J:173397)
• abnormal long term depression
  • glutamate receptor long term depression (mGluR-LTD) induced by DHPG is increased and inhibited by cycloheximide compared to in wild-type mice   (MGI Ref ID J:173397)
  • LTD induced by paired-pulse low-frequency stimulation is increased compared to in wild-type mice   (MGI Ref ID J:173397)
• decreased synaptic depression
  • NMDAR-dependent long term depression of Schaffer collateral-CA1 synapses is reduced compared to in wild-type mice   (MGI Ref ID J:173397)
• reduced long term potentiation
  • NMDAR-dependent long term potentiation induction magnitude is reduced and decays more rapidly than in wild-type mice   (MGI Ref ID J:173397)

View Research Applications

Research Applications

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

Neurobiology Research
Neurodevelopmental Defects
      Autism

Genes & Alleles

Gene & Allele Information provided by MGI

Allele Symbol		Shank3tm1.1Pfw
Allele Name		targeted mutation 1.1, Paul Worley
Allele Type		Targeted (other)
Common Name(s)		Shank3(deltaC); Shank3tm1.1Bxia;
Mutation Made By		Bo Xiao,   Johns Hopkins University School of Medic
Strain of Origin		129S6/SvEvTac
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 21. An FRT-flanked neo cassette with a 3' loxP site was inserted downstream of exon 21. Cre-mediated recombination removed exon 21 and the neo cassette. [MGI Ref ID J:173397]

Genotyping

Genotyping Information

Genotyping Protocols

Shank3^tm1.1Pfw, Separated PCR

Helpful Links

Genotyping resources and troubleshooting

References

References provided by MGI

Selected Reference(s)

Bangash MA; Park JM; Melnikova T; Wang D; Jeon SK; Lee D; Syeda S; Kim J; Kouser M; Schwartz J; Cui Y; Zhao X; Speed HE; Kee SE; Tu JC; Hu JH; Petralia RS; Linden DJ; Powell CM; Savonenko A; Xiao B; Worley PF. 2011. Enhanced Polyubiquitination of Shank3 and NMDA Receptor in a Mouse Model of Autism. Cell 145(5):758-72. [PubMed: 21565394]  [MGI Ref ID J:173397]

Health & husbandry

Health & Colony Maintenance Information

Animal Health Reports

Room Number           AX18

Colony Maintenance

Breeding & Husbandry	When maintaining a live colony, heterozygous males may be bred to wildtype females from the colony or to C57BL/6J female mice (Stock No. 000664). The donating investigator maintains this non-reciprocal cross to exclude effects of possible maternal autism spectrum disorder (ASD)-like phenotype on rearing. Some fertility issues have been reported when maintaining a homozygous colony.
Mating System	+/+ sibling x Heterozygote         (Female x Male)   07-AUG-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.

Important Note

The reference originally describing this allele (Cell 145:758-72) has been retracted. The donating investigator has confirmed that the basis of the retraction is not related to the identity, structure or phenotype of this exon 21 deletion mutant.

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