Overview

Also Known As:SYNGAP1^lx-st (Cre-conditional rescue)

The SYNGAP1^lx-st conditional rescue knock-in allele has a loxP-flanked neo-STOP cassette upstream of exon 6 of the synaptic RasGAP (SynGAP) gene; resulting in disrupted expression of full-length SynGAP and expression of a truncated/inactive SynGAP protein. These mice allow Cre recombinase-inducible restoration of full-length SynGAP expression. SYNGAP1^lx-st mice may be useful Cre-lox studies of synapse development (specifically in dendritic spine), cognitive and behavioral maturation, intellectual disability and autism spectrum disorder.

Donating Investigator

Gavin Rumbaugh, The Scripps Research Institute

Genetic overview

Genetic Background	Generation

Syngap1^tm2Geno

Allele Type	Gene Symbol	Gene Name
Targeted (Inserted expressed sequence, Humanized sequence)	Syngap1	synaptic Ras GTPase activating protein 1 homolog (rat)

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Research Applications

Neurobiology Research
Developmental Biology Research
Research Tools

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Base Price

Starting at:

$2,854.50 Domestic price Cryo Recovery

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Details

Detailed Description

Mutations that cause intellectual disability (ID) and autism spectrum disorder (ASD) are commonly found in genes that encode for synaptic proteins. Syngap1 encodes a synaptic RasGAP (SynGAP) that is largely localized to dendritic spines in neocortical pyramidal neurons, where it suppresses signaling pathways linked to NMDA receptor (NMDAR)-mediated synaptic plasticity and AMPA receptor (AMPAR) membrane insertion. Syngap1 has alternative transcriptional start sites and several alternatively spliced C-terminal exons that result in many possible SynGAP isoforms. Human SYNGAP1 haploinsufficiency results from a truncation of the full-length protein. Exon 7 contains the first common methionine present in the shortest splice variant.

The SYNGAP1^lx-st allele has a loxP-flanked neo-STOP cassette upstream of exon 6 of the Syngap1 gene. Following cre-mediated recombination that removes the floxed region, SynGAP expression and function are fully recovered.

Prior to Cre recombinase exposure, mice heterozygous for the SYNGAP1^lx-st allele express a SynGAP protein truncated after exon 5 (known to be an inactivate SynGAP protein), as well as diminished levels of functional SynGAP (from the wildtype allele). Therefore, the phenotype of heterozygotes (SYNGAP1^lx-st/+) is the same as mice heterozygous for the global knockout allele, and both are a model of human SYNGAP1 haploinsufficiency - exhibiting normal synaptic transmission, modest defects in synaptic plasticity, enhanced synaptic function (accelerated rate of glutamatergic synapse maturation) during early neural development and profound cognitive and behavioral abnormalities. Specifically, heterozygous SynGAP-deficiency significantly disrupts excitatory/inhibitory (E/I) balance in the neural networks that support cognition and behavior. Abnormal behavioral phenotypes can be observing as early as 21 days of age with ~100% penetrance (although physiological abnormalities can be measured even earlier through other methods such as electrophysiological recordings). Furthermore, homozygotes (SYNGAP1^lx-st/lx-st are phenotypically the same as global knockout homozygotes - exhibiting complete postnatal lethality between 2-5 days of age.

When SYNGAP1^lx-st are bred to mice that express Cre recombinase, the resulting offspring may be useful in generating tissue-specific restoration of full-length SynGAP expression. For example, when SYNGAP1^lx-st/+ mice are bred hemizygous for the CAGGCre-ER^TM transgene (Stock No. 004682), the resulting animals allow widespread, tamoxifen-inducible SynGAP restoration. In those mice, complete restoration of SynGAP protein expression in adults had no detectable benefit on behavior or cognition - demonstrating that SYNGAP1 haploinsufficiency is a disorder of brain development.

Development

The SYNGAP1 conditional rescue mice (SYNGAP1^lx-st) was constructed by genOway S.A. (France) as a pay-for-service on behalf of Dr. Gavin Rumbaugh (The Scripps Research Institute).
The targeting vector was designed to insert a loxP-flanked STOP cassette (neomycin resistance gene and a series of stop codons) immediately downstream of exon 5 of the synaptic Ras GTPase activating protein 1 homolog (rat) locus (Syngap1) on chromosome 17.

The construct was electroporated into 129S2/SvPas-derived embryonic stem (ES) cells. Correctly targeted ES cells were identified and injected into recipient blastocysts. Chimeric males were bred to C57BL/6J for germline transmission.

The SYNGAP1^lx-st colony was maintained on this mixed genetic background for several generations prior to sending males (with black or agouti coat color) to The Jackson Laboratory Repository in 2012.

Upon arrival, males were used to cryopreserve sperm. To establish a living mouse colony, an aliquot of the frozen sperm may be used to fertilize oocytes from C57BL/6J inbred females (Stock No. 000664).

Expression Data

Expressed Gene	Syngap1, synaptic Ras GTPase activating protein 1 homolog (rat), mouse, laboratory
Site of Expression

Control Suggestions

Wild-type from the colony

Additional Information

Considerations for Choosing Controls

Selected References

Clement JP; Aceti M; Creson TK; Ozkan ED; Shi Y; Reish NJ; Almonte AG; Miller BH; Wiltgen BJ; Miller CA; Xu X; Rumbaugh G. 2012. Pathogenic SYNGAP1 mutations impair cognitive development by disrupting maturation of dendritic spine synapses. Cell 151(4):709-23PubMed: 23141534 MGI: J:193208

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Genetics

Syngap1^tm2Geno

Allele Symbol: Syngap1^tm2Geno

Allele Name	targeted mutation 2, Genoway
Allele Type	Targeted (Inserted expressed sequence, Humanized sequence)
Allele Synonym(s)	targeted mutation 2, Genoway; Syngap1^tm2Geno
Gene Symbol and Name	Syngap1, synaptic Ras GTPase activating protein 1 homolog (rat)
Gene Synonym(s)	RASA1; RASA5; SYNGAP; gene model 1963, (NCBI); MRD5; Gm1963; Syngap
Expressed Gene	Syngap1, synaptic Ras GTPase activating protein 1 homolog (rat), mouse, laboratory
Strain of Origin	129S2/SvPas
Chromosome	17
Molecular Note	A floxed neo cassette was inserted into intron 5. Western blot analysis confirmed reduced protein expression in heterozygous samples. Cre-mediated recombination is required to remove the neo cassette and restore protein expression.

Disease/Phenotype

Disease Terms

Research Areas By Phenotype

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

Neurobiology Research
- Behavioral and Learning Defects
- Channel and Transporter Defects
  - calcium: glutamate receptor
- Receptor Defects
  - glutamate receptor: NMDA
- Neurotransmitter Receptor and Synaptic Vesicle Defects
- Neurodevelopmental Defects
  - Autism
- Cre-lox System
  - loxP-flanked Sequences
Developmental Biology Research
- Neurodevelopmental Defects
- Postnatal Lethality
  - Homozygous
Research Tools
- Cre-lox System
  - loxP-flanked Sequences
- Developmental Biology Research
  - Cre-lox System
- Genetics Research
  - Mutagenesis and Transgenesis: Cre-lox System

Mammalian Phenotype Terms by Genotype

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

Genotype: Syngap1^tm2Geno/Syngap1⁺ Tg(CAG-cre/Esr1)5Amc/0
involves: 129S2/SvPas C57BL/6 * CBA

behavior/neurological phenotype

abnormal behavior
- mice exhibit behavioral abnormalities as in Syngap1^tm1Rlh heterozygotes

abnormal spatial working memory
- untreated mice and mice treated with tamoxifen in adulthood exhibit absence of spontaneous alteration in a T-maze compared with control mice

decreased anxiety-related response
- untreated mice and mice treated with tamoxifen in adulthood spend increased time in open arms of an elevated plus maze compared with control mice

hyperactivity
- untreated mice and mice treated with tamoxifen in adulthood exhibit increased activity in an open field compared with control mice

References

Clement JP; Aceti M; Creson TK; Ozkan ED; Shi Y; Reish NJ; Almonte AG; Miller BH; Wiltgen BJ; Miller CA; Xu X; Rumbaugh G. 2012. Pathogenic SYNGAP1 mutations impair cognitive development by disrupting maturation of dendritic spine synapses. Cell 151(4):709-23PubMed: 23141534 MGI: J:193208

Additional - Syngap1^tm2Geno related

Technical Support

CONTACT TECHNICAL SUPPORT

Genotyping Protocols
- Separated PCR:Syngap1-Alternate 2
- Standard PCR:Generic Neo
- Probe:Generic Neo
- Genotyping resources and troubleshooting
Breeding Considerations

Homozygous mice exhibit complete postnatal lethality between 2-5 days of age. Heterozygous mice develop profound cognitive and behavioral abnormalities grossly demonstrable ~21 days of age. The donating investigator breeds heterozygous mice to wildtype mice from the colony, using both sexes as the heterozygote.

When maintaining a live colony, at The Jackson Laboratory Repository, heterozygous mice may be bred to wildtype mice from the colony or to C57BL/6J inbred mice (Stock No. 000664).
- Additional Breeding and Husbandry Support
Mating System
- Wild-type x Heterozygote
- Heterozygote x Wild-type
Citation
When using the SYNGAP1^lx-st (Cre-conditional rescue) mouse strain in a publication, please cite the originating article(s) and include JAX stock #029304 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 Syngap1<tm2Geno>

Related Products and Services

Frozen Mouse Embryo	B6;129S2-Syngap1<tm2Geno>/RumbJ Frozen Embryo	$2595.00
Frozen Mouse Embryo	B6;129S2-Syngap1<tm2Geno>/RumbJ Frozen Embryo	$2595.00
Frozen Mouse Embryo	B6;129S2-Syngap1<tm2Geno>/RumbJ Frozen Embryo	$3373.50
Frozen Mouse Embryo	B6;129S2-Syngap1<tm2Geno>/RumbJ Frozen Embryo	$3373.50

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Also Known As:SYNGAP1lx-st (Cre-conditional rescue)

Donating Investigator

Genetic overview

Research Applications

Base Price

Detailed Description

Development

Expression Data

Control Suggestions

Additional Information

Selected References

Syngap1tm2Geno

Allele Symbol: Syngap1tm2Geno

Disease Terms

Research Areas By Phenotype

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

Mammalian Phenotype Terms by Genotype

Genotype: Syngap1tm2Geno/Syngap1+ Tg(CAG-cre/Esr1*)5Amc/0involves: 129S2/SvPas * C57BL/6 * CBA

behavior/neurological phenotype

References

Additional - Syngap1tm2Geno related

Genotyping Protocols

Breeding Considerations

Mating System

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:SYNGAP1^lx-st (Cre-conditional rescue)

Syngap1^tm2Geno

Allele Symbol: Syngap1^tm2Geno

Genotype: Syngap1^tm2Geno/Syngap1⁺ Tg(CAG-cre/Esr1)5Amc/0
involves: 129S2/SvPas C57BL/6 * CBA

Additional - Syngap1^tm2Geno related