Overview

Also Known As:Shank3^ΔC (Shank3^{Δ ex21})

These Shank3(+/ΔC) mice may be useful for studying behavioral and synaptic abnormalities associated with autism spectrum disorder.

Donating Investigator

Paul Worley, Johns Hopkins University School of Medic

Genetic overview

Genetic Background	Generation

Shank3^tm1.1Pfw

Allele Type	Gene Symbol	Gene Name
Targeted (Hypomorph)	Shank3	SH3 and multiple ankyrin repeat domains 3

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Research Applications

Neurobiology Research

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Base Price

Starting at:

$2,854.50 Domestic price Cryo Recovery

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Details

Detailed 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 Suggestions

Wild-type from the colony

Approximate Controls

000664 C57BL/6J

Additional Information

Considerations for Choosing Controls

Genetics

Shank3^tm1.1Pfw

Allele Symbol: Shank3^tm1.1Pfw

Allele Name	targeted mutation 1.1, Paul Worley
Allele Type	Targeted (Hypomorph)
Allele Synonym(s)	Shank3(deltaC); Shank3^tm1.1Bxia
Gene Symbol and Name	Shank3, SH3 and multiple ankyrin repeat domains 3
Gene Synonym(s)
Strain of Origin	129S6/SvEvTac
Chromosome	15
General Note	The data reported for this allele were originally described in: 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. Enhanced polyubiquitination of Shank3 and NMDA receptor in a mouse model of autism. Cell. 2011 May 27;145(5):758-72. PMID:21565394. This paper was retracted; however, the prinicpal investigator has confirmed the validity of the data related to the molecular gene targeting and the phenotypic description of the mutant mice carrying this allele. Please see the retraction notes for further details about the data in the original paper.
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. No wild-type protein is detected in homozygous mice but a lower molecular weight mutant protein is detected by western blot analysis.
Mutations Made By	Bo Xiao, Johns Hopkins University School of Medic

Disease/Phenotype

Disease Terms

Models with phenotypic similarity to human diseases where etiology is unknown or involving genes where ortholog is unknown.

autism spectrum disorder

Research Areas By Phenotype

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

Neurobiology Research
- Neurodevelopmental Defects
  - Autism

Mammalian Phenotype Terms by Genotype

The following phenotype relates to a compound genotype created using this strain

Genotype: Shank3^tm1.1Pfw/Shank3⁺
B6.129S6-Shank3

behavior/neurological phenotype

abnormal social investigation
- Normal - however, mice exhibit normal social recognition memory
- male mice exhibit increased latency to approach a sexually receptive enclosed female mouse compared with wild-type mice
- male mice spend more time investigating an enclosed male stimulus compared with wild-type mice
- mice exhibit reduced social investigation modulated by episodes of aggression compared with wild-type mice

abnormal social/conspecific interaction
- mice exhibit reduced social investigation modulated by episodes of aggression compared with wild-type mice

abnormal vocalization
- male mice exhibit latency to first ultrasound call in the presence of a female mice compared with wild-type mice

decreased startle reflex
- mice exhibit lower amplitudes and longer latencies of startle response compared with wild-type mice

increased aggression towards mice
- mice exhibit increased aggression towards a novel stimulus mouse and in a resident-intruder tests compared with wild-type mice

induced hyperactivity
- Normal - however, mice do not exhibit novelty-induced hyperactivity
- in dizocilpine- or amphetamine-treated mice

mammalian phenotype

behavior/neurological phenotype
- Normal - 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

nervous system phenotype

abnormal glutamate-mediated receptor currents
- Normal - however, AMPAR-mediated miniature excitatory postsynaptic current amplitude and frequency are normal
- the ratio of NMDA to AMPA-dependent response in the cortex is reduced compared to in wild-type mice

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
- LTD induced by paired-pulse low-frequency stimulation is increased compared to in wild-type mice

decreased synaptic depression
- NMDAR-dependent long term depression of Schaffer collateral-CA1 synapses is reduced compared to in wild-type mice

reduced long term potentiation
- NMDAR-dependent long term potentiation induction magnitude is reduced and decays more rapidly than in wild-type mice

reduced NMDA-mediated synaptic currents

Genotype: Shank3^tm1.1Pfw/Shank3^tm1.1Pfw
B6.129S6-Shank3

behavior/neurological phenotype

abnormal innate avoidance response
- however, mice do not show increased anxiety-like behaviors in elevated plus maze or open field assays, suggesting this is an avoidance of light rather than an anxiety-like behavior
- remarkable increase in avoidance of a brightly lit chamber in a dark/light chamber assay spending almost the entire 10 min assay time in the dark chamber

abnormal motor coordination/balance
- increased swim speed in females

abnormal response to novel object
- fail to interact with inanimate objects in nest building and marble burying assays
- interact significantly less with an inanimate object in a three-chamber social interaction assay

abnormal response to novelty
- show no preference for social novelty versus familiarity

abnormal social investigation
- show no preference for social novelty versus familiarity

abnormal spatial reference memory
- in a reversal learning water maze test mice fail to show any preference for the new target location in the probe trial

decreased exploration in new environment
- decrease locomotor behavior for the first 5 min in a novel home cage, this rapidly reverts to wild-type levels after the first 5 min

decreased thermal nociceptive threshold
- decreased latency in a hotplate assay

impaired coordination
- decrease in latency to fall in a rotarod assay

impaired spatial learning
- in a Morris water maze
- in a reversal learning water maze test mice fail to show any preference for the new target location in the probe trial

increased grooming behavior
- increase in grooming and time spent per grooming bout in older (10-13 months of age) but not younger (9-18 weeks of age) mice

photophobia
- however, mice do not show increased anxiety-like behaviors in elevated plus maze or open field assays, suggesting this is an avoidance of light rather than an anxiety-like behavior
- remarkable increase in avoidance of a brightly lit chamber in a dark/light chamber assay spending almost the entire 10 min assay time in the dark chamber

growth/size/body region phenotype

decreased body weight
- at about 17 weeks of age

homeostasis/metabolism phenotype

photophobia
- however, mice do not show increased anxiety-like behaviors in elevated plus maze or open field assays, suggesting this is an avoidance of light rather than an anxiety-like behavior
- remarkable increase in avoidance of a brightly lit chamber in a dark/light chamber assay spending almost the entire 10 min assay time in the dark chamber

integument phenotype

decreased thermal nociceptive threshold
- decreased latency in a hotplate assay

mammalian phenotype

behavior/neurological phenotype
- Normal - do not show communication deficits or abnormalities in startle response

nervous system phenotype
- Normal - the number and structure of CA1 pyramidal neuron synaptic spines are similar to controls

nervous system phenotype

abnormal excitatory postsynaptic currents
- the input/output relationship of stimulus intensity to slope of the fEPSP is decreased

abnormal glutamate-mediated receptor currents
- decrease in the NMDA/AMPA ratio in hippocampal synapses

abnormal miniature excitatory postsynaptic currents
- frequency is significantly decreased; however, amplitude is similar to controls

reduced long term potentiation
- significantly impaired

vision/eye phenotype

photophobia
- however, mice do not show increased anxiety-like behaviors in elevated plus maze or open field assays, suggesting this is an avoidance of light rather than an anxiety-like behavior
- remarkable increase in avoidance of a brightly lit chamber in a dark/light chamber assay spending almost the entire 10 min assay time in the dark chamber

References

Additional - Shank3^tm1.1Pfw related

Technical Support

CONTACT TECHNICAL SUPPORT

Genotyping Protocols
- Separated PCR:Shank3
- Genotyping resources and troubleshooting
Breeding Considerations

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.
- Additional Breeding and Husbandry Support
Citation
When using the Shank3^ΔC (Shank3^{Δ ex21}) mouse strain in a publication, please cite the originating article(s) and include JAX stock #018398 in your Materials and Methods section.

Animal Health Reports

Facility Barrier Level Descriptions

Production of mice from cryopreserved embryos or sperm occurs in a maximum barrier room, G200

Pricing & Availability

Cryo Recovery

Domestic
International

Live Mouse

Age

Genotype

Price

weeks

Cryorecovery - Pricing

Service/Product	Description	Price
	Heterozygous or wildtype for Shank3<tm1.1Pfw>

Related Products and Services

Frozen Mouse Embryo	STOCK Shank3<tm1.1Pfw>/J Frozen Embryo	$2595.00
Frozen Mouse Embryo	STOCK Shank3<tm1.1Pfw>/J Frozen Embryo	$2595.00
Frozen Mouse Embryo	STOCK Shank3<tm1.1Pfw>/J Frozen Embryo	$3373.50
Frozen Mouse Embryo	STOCK Shank3<tm1.1Pfw>/J Frozen Embryo	$3373.50

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Also Known As:Shank3ΔC (Shank3Δ ex21)

Donating Investigator

Genetic overview

Research Applications

Base Price

Detailed Description

Development

Control Suggestions

Approximate Controls

Additional Information

Shank3tm1.1Pfw

Allele Symbol: Shank3tm1.1Pfw

Disease Terms

Models with phenotypic similarity to human diseases where etiology is unknown or involving genes where ortholog is unknown.

Research Areas By Phenotype

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

Mammalian Phenotype Terms by Genotype

Genotype: Shank3tm1.1Pfw/Shank3+B6.129S6-Shank3

behavior/neurological phenotype

mammalian phenotype

nervous system phenotype

Genotype: Shank3tm1.1Pfw/Shank3tm1.1PfwB6.129S6-Shank3

behavior/neurological phenotype

growth/size/body region phenotype

homeostasis/metabolism phenotype

integument phenotype

mammalian phenotype

nervous system phenotype

vision/eye phenotype

References

Additional - Shank3tm1.1Pfw related

Genotyping Protocols

Breeding Considerations

Citation

Animal Health Reports

Production of mice from cryopreserved embryos or sperm occurs in a maximum barrier room, G200

Live Mouse

Cryorecovery - Pricing

Related Products and Services

Payment Terms and Conditions

The Jackson Laboratory's Genotype Promise

Terms Of Use

Licensing Information

JAX® Mice, Products & Services Conditions of Use

No Warranty

Credit for PRODUCTS or SERVICES

Animal Care and Use for SERVICES

No Liability

Also Known As:Shank3^ΔC (Shank3^{Δ ex21})

Shank3^tm1.1Pfw

Allele Symbol: Shank3^tm1.1Pfw

Genotype: Shank3^tm1.1Pfw/Shank3⁺
B6.129S6-Shank3

Genotype: Shank3^tm1.1Pfw/Shank3^tm1.1Pfw
B6.129S6-Shank3

Additional - Shank3^tm1.1Pfw related