Overview

Also Known As:R1117X Shank3 (Shank3*R1117X knock-in)

The R1117X Shank3 knock-in allele (Shank3*R1117X) harbors the schizophrenia-associated R1117X mutation in Shank3 exon 21 that results in expression of a ~122 kDa truncated SHANK3 protein. Homozygous mice exhibit profound synaptic defects in prefrontal cortex, social dominance behavior and increased level of anxiety-like behavior.

Donating Investigator

Guoping Feng, Massachusetts Institute of Technology

Genetic overview

Genetic Background	Generation

Shank3^tm4.1Gfng

Allele Type	Gene Symbol	Gene Name
Targeted (Not Applicable)	Shank3	SH3 and multiple ankyrin repeat domains 3

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Research Applications

Neurobiology Research
Research Tools
Developmental Biology Research

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Base Price

Starting at:

$2,854.50 Domestic price Cryo Recovery

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Details

Detailed Description

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.

The R1117X Shank3 knock-in allele harbors the schizophrenia-associated R1117X mutation in Shank3 exon 21 that creates a stop codon and results in expression of a ~122 kDa truncated SHANK3 protein.

R1117X Shank3 mice on a mixed C57BL/6J;129S genetic background were characterized in the original publication (Zhou et al. 2016 Neuron 89:147); and this is described below.
The donating investigator reports that mice homozygous for the R1117X Shank3 knock-in allele (R1117X^+/+) are viable and fertile, but are inefficient breeders. Homozygotes exhibit synaptic and behavioral phenotypes similar to human schizophrenia. Specifically, R1117X^+/+ exhibit profound synaptic defects in prefrontal cortex, social dominance behavior and increased level of anxiety-like behavior. Heterozygous mice (R1117X^+/-) have ~50% of the wildtype levels of full-length SHANK3 protein, and exhibit a less severe phenotype.

Development

The R1117X Shank3 knock-in allele (Shank3*R1117X) was designed by Dr. Guoping Feng (Massachusetts Institute of Technology) to alter exon 21 of the SH3/ankyrin domain gene 3 (Shank3) on chromosome 15 by changing the DNA sequence of codon 1117 from CGG-to-TGA (arginine-to-stop codon). This R1117X non-sense mutation was first identified in three brothers diagnosed with schizophrenia/schizoaffective disorder between ages 16 and 21 (also with mild-to-moderate mental retardation) without showing obvious autistic features during their childhood. A loxP-flanked PGK-neo-pA cassette was also inserted downstream of the mutant stop codon (but was later removed as described below). The targeting vector was co-electroporated with a pair of TALE nuclease plasmids (designed to facilitate recombination) into 129X1/SvJ x 129S1/Sv)F1-Kitl⁺-derived R1 embryonic stem (ES) cells. Correctly targeted ES cells were injected into recipient blastocysts. Chimeric mice were bred with C57BL/6J for germline transmission and to establish the colony. The PGK-neo-pA cassette was deleted by breeding to C57BL/6 mice with germline Cre recombinase expression.
The resulting R1117X Shank3 mice were backcrossed to C57BL/6J inbred mice (Stock No. 000664) for at least five or six generations (during which the Cre recombinase allele was removed). Next, they were bred to 129S1/SvImJ inbred mice (Stock No. 002448) for at least one generation.

R1117X Shank3 mice on this mixed C57BL/6J;129S genetic background were characterized in the original publication (Zhou et al. 2016 Neuron 89:147), and males with agouti coat color were sent to The Jackson Laboratory Repository in 2016. Upon arrival, sperm was cryopreserved.

To establish our live colony, an aliquot of frozen sperm was used to fertilize B6129SF1 oocytes (Stock No. 101043).

Control Suggestions

Wild-type from the colony

Approximate Controls

101045 B6129SF2/J

Additional Information

Considerations for Choosing Controls

Selected References

Zhou Y; Kaiser T; Monteiro P; Zhang X; Van der Goes MS; Wang D; Barak B; Zeng M; Li C; Lu C; Wells M; Amaya A; Nguyen S; Lewis M; Sanjana N; Zhou Y; Zhang M; Zhang F; Fu Z; Feng G. 2016. Mice with Shank3 Mutations Associated with ASD and Schizophrenia Display Both Shared and Distinct Defects. Neuron 89(1):147-62PubMed: 26687841 MGI: J:230887

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Genetics

Shank3^tm4.1Gfng

Allele Symbol: Shank3^tm4.1Gfng

Allele Name	targeted mutation 4.1, Guoping Feng
Allele Type	Targeted (Not Applicable)
Allele Synonym(s)	R1117X
Gene Symbol and Name	Shank3, SH3 and multiple ankyrin repeat domains 3
Gene Synonym(s)
Strain of Origin	(129X1/SvJ x 129S1/Sv)F1-Kitl⁺
Chromosome	15
Molecular Note	The targeting vector was designed to alter exon 21 by changing the DNA sequence of codon 1117 from CGG-to-TGA (arginine-to-stop codon) resulting in a truncated 122 kDa protein. A loxP-flanked PGK-neo-pA cassette was also inserted downstream of the mutant stop codon. Cre-mediated recombination removed the floxed neo cassette. This non-sense mutation was first identified in three brothers diagnosed with schizophrenia/schizoaffective disorder between ages 16 and 21 (also with mild-to-moderate mental retardation) without showing obvious autistic features during their childhood.

Disease/Phenotype

Disease Terms

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).

schizophrenia

Research Areas By Phenotype

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

Neurobiology Research
- Behavioral and Learning Defects
- Neurodevelopmental Defects
Research Tools
- Developmental Biology Research
- Neurobiology Research
Developmental Biology Research
- Neurodevelopmental Defects

Mammalian Phenotype Terms by Genotype

The following phenotype information is associated with a similar, but not exact match to this JAX^® Mice strain

Genotype: Shank3^tm4.1Gfng/Shank3^tm4.1Gfng
involves: 129S1/Sv * 129X1/SvJ * C57BL/6J

behavior/neurological phenotype

abnormal motor learning
- impaired motor learning in rotarod test

abnormal social investigation
- mice exhibit no preference for a stranger mouse or novel object in a test of voluntary social interaction

abnormal startle reflex
- impaired acoustic startle response

decreased exploration in new environment
- decreased total distance travelled in open field test as compared to controls

hypoactivity

impaired coordination
- impaired motor coordination in rotarod test

increased aggression towards mice
- increased social dominance behavior as determined by tube test

increased anxiety-related response
- mice spend less time exploring center of open area test than controls
- mice spend less time in open arm during elevated zero maze test

increased grooming behavior
- 8.7% of mice develop lesions from grooming between 4 and 6 months
- amount of time grooming is not significantly different than controls although a trend of increase is observed

nervous system phenotype

abnormal dendritic spine morphology
- reduction in spine density of layer 2/3 pyramidal neurons in prefrontal cortex

abnormal miniature excitatory postsynaptic currents
- mEPSC frequency is increased in the prefrontal cortex at P14
- reduced mEPSC amplitude in prefrontal cortex in adult mice
- reduced mEPSC frequency in medium spiny neurons from adult mice as compared to controls
- reduced mEPSC frequency in pyramidal neurons of prefrontal cortex in adult mice as compared to controls
- small, but significant, reduction of mEPSC amplitude in medium spiny neurons from adult mice as compared to controls

abnormal paired-pulse inhibition
- slightly impaired pulse inhibition (PPI)

decreased excitatory postsynaptic current amplitude
- presynaptic function is not affected
- reduced striatal field pop spike amplitude in adults as compared to controls

reduced NMDA-mediated synaptic currents
- reduced NMDA receptor-mediated currents as compared to controls

Genotype: Shank3^tm4.1Gfng/Shank3⁺
involves: 129S1/Sv * 129X1/SvJ * C57BL/6J

behavior/neurological phenotype

abnormal social investigation
- mice exhibit no preference for a stranger mouse or novel object in a test of voluntary social interaction

increased anxiety-related response
- mice spend less time in open arm during elevated zero maze test

nervous system phenotype

abnormal dendritic spine morphology
- reduction in spine density of layer 2/3 pyramidal neurons in prefrontal cortex

abnormal miniature excitatory postsynaptic currents
- reduced mEPSC frequency in pyramidal neurons of prefrontal cortex as compared to controls
- small, but significant, reduction of mEPSC amplitude in medium spiny neurons from adult mice as compared to controls

References

Zhou Y; Kaiser T; Monteiro P; Zhang X; Van der Goes MS; Wang D; Barak B; Zeng M; Li C; Lu C; Wells M; Amaya A; Nguyen S; Lewis M; Sanjana N; Zhou Y; Zhang M; Zhang F; Fu Z; Feng G. 2016. Mice with Shank3 Mutations Associated with ASD and Schizophrenia Display Both Shared and Distinct Defects. Neuron 89(1):147-62PubMed: 26687841 MGI: J:230887

Additional - Shank3^tm4.1Gfng related

Technical Support

CONTACT TECHNICAL SUPPORT

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

The donating investigator reports that although homozygous mice are viable and fertile, their synaptic and behavioral abnormalities result in inefficient breeding. When maintaining a live colony, heterozygous mice may be bred together, to wildtype littermates, or to B6129SF1 mice (Stock No. 101043).
- Additional Breeding and Husbandry Support
Citation
When using the R1117X Shank3 (Shank3*R1117X knock-in) mouse strain in a publication, please cite the originating article(s) and include JAX stock #028779 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<tm4.1Gfng>

Related Products and Services

Frozen Mouse Embryo	STOCK Shank3<tm4.1Gfng>/J	$2595.00
Frozen Mouse Embryo	STOCK Shank3<tm4.1Gfng>/J	$2595.00
Frozen Mouse Embryo	STOCK Shank3<tm4.1Gfng>/J	$3373.50
Frozen Mouse Embryo	STOCK Shank3<tm4.1Gfng>/J	$3373.50

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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. We do not guarantee breeding performance and therefore suggest that investigators order more than one breeding pair to avoid delays in their research.

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Also Known As:R1117X Shank3 (Shank3*R1117X knock-in)

Donating Investigator

Genetic overview

Research Applications

Base Price

Detailed Description

Development

Control Suggestions

Approximate Controls

Additional Information

Selected References

Shank3tm4.1Gfng

Allele Symbol: Shank3tm4.1Gfng

Disease Terms

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).

Research Areas By Phenotype

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

Mammalian Phenotype Terms by Genotype

Genotype: Shank3tm4.1Gfng/Shank3tm4.1Gfnginvolves: 129S1/Sv * 129X1/SvJ * C57BL/6J

behavior/neurological phenotype

nervous system phenotype

Genotype: Shank3tm4.1Gfng/Shank3+involves: 129S1/Sv * 129X1/SvJ * C57BL/6J

behavior/neurological phenotype

nervous system phenotype

References

Additional - Shank3tm4.1Gfng 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

Additional Use Restrictions Apply

Licensing Information

JAX® Mice, Products & Services Conditions of Use

No Warranty

Credit for PRODUCTS or SERVICES

Animal Care and Use for SERVICES

No Liability

Shank3^tm4.1Gfng

Allele Symbol: Shank3^tm4.1Gfng

Genotype: Shank3^tm4.1Gfng/Shank3^tm4.1Gfng
involves: 129S1/Sv * 129X1/SvJ * C57BL/6J

Genotype: Shank3^tm4.1Gfng/Shank3⁺
involves: 129S1/Sv * 129X1/SvJ * C57BL/6J

Additional - Shank3^tm4.1Gfng related