Overview

Also Known As: Gtf2i duplication (Gtf2i^Dup)

The Gtf2i duplication allele (Gtf2i^Dup) has one additional copy of a functional mouse general transcription factor 2I gene (TFII-I). These mice model characteristics of 7q11.23 duplication syndrome (Dup7q11.23), and may be useful for studying the cellular mechanisms underlying GTF2I-related neurodevelopmental disorders and molecular separation-anxiety pathways.

Donating Investigator

Lucy R Osborne, University of Toronto

Genetic overview

Genetic Background	Generation

Dp(5Gtf2i-Gtf2ird1)1Lro

Allele Type	Gene Symbol	Gene Name
Targeted (Not Applicable)	Dp(5Gtf2i-Gtf2ird1)1Lro	duplication, Chr 5, L Osborne 1

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Research Applications

Developmental Biology Research
Neurobiology Research
Cell Biology Research

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Base Price

Starting at:

$2,854.50 Domestic price Cryo Recovery

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Details

Detailed Description

The Gtf2i duplication allele (Gtf2i^Dup; Dp(5Gtf2i-Gtf2ird1)1Lro) has one additional copy of a functional mouse Gtf2i gene (and a non-functional Gtf2ird1 allele) inserted centromeric to the endogenous general transcription factor 2I locus (GTF2I; encoding protein TFII-I).

TFII-I is a transcriptional activator that regulates neuronal maturation and intracellular Ca2+ levels (through the TRPC3 channel), and is highly expressed in the prenatal and postnatal developing brain. The human chromosome 7 locus, 7q11.23, is a 1.5-1.8 Mbp region susceptible to genomic rearrangement through non-allelic homologous recombination. This region contains ~25 protein coding genes; including GTF2I. 7q11.23 duplication syndrome (Dup7q11.23) and 7q11.23 deletion syndrome (Williams-Beuren Syndrome [WBS]) are neurodevelopmental disorders with unique/contrasting cognitive and behavioral profiles. In humans, Dup7q11.23 is associated with speech and language delay, anxiety (both social and nonsocial) and autism. Some individuals exhibit macrocephaly and increased brain volume, as well as cortical dysplasia. Approximately 30% of 4- to 12-year-olds with Dup7q11.23 may meet diagnostic criteria for a separation-anxiety disorder.

Mice that are wildtype (Gtf2i^+/+), hemizygous (Gtf2i^Dup/+) and homozygous (Gtf2i^Dup/Dup) for the Gtf2i duplication allele harbor a total of two, three and four Gtf2i copies, respectively.
When compared to mouse pups with one Gtf2i copy (heterozygous for a knockout allele) or two Gtf2i copies (wildtype), pups with additional Gtf2i copies (hemizygous and homozygous mice) show significantly increased maternal separation-induced anxiety as measured by ultrasonic vocalizations.
Copy number alterations of GTF2I affect cortical neuronal morphology/maturation, novel object recognition and agonist-induced calcium entry (calcium signaling via the TRPC3 channel). Specifically, Gtf2i^Dup/+ mice exhibit deficits in a cortically-dependent learning and memory task (novel object recognition). Ca2+ influx via neuronal TRPC3 channels is decreased in Gtf2i^Dup/+ (whereas it is increased in mice heterozygous for a knockout allele).

The donating investigator reports hemizygous and homozygous mice are viable and fertile with healthy nutritional status. When maintaining their colony by breeding wildtype (noncarrier) females with hemizygous males, they report the mice are good breeders with no reduced survival. They also report no GTF2IRD1 expression from the additional copy of the Gtf2ird1 allele (i.e., the additional copy of Gtf2ird1 is a functional null).

Development

The Gtf2i duplication allele (Gtf2i^Dup; Dp(5Gtf2i-Gtf2ird1)1Lro) was created by Dr. Lucy R. Osborne (University of Toronto) by first obtaining two independent mouse lines with loxP sites at the desired endpoints, and then using Cre recombinase expression during male meiosis to generate a chromosome with one additional copy of a functional Gtf2i gene. Specific details are below.

The Gtf2i^3'UTRloxP allele (Gtf2i^tm1Lro) was created by Dr. Osborne using a 5' hprt vector to place a loxP site and neo cassette into the 3' UTR of the general transcription factor II I locus (Gtf2i) on chromosome 5. The construct was electroporated into (129X1/SvJ x 129S1/Sv)F1-Kitl⁺ derived R1 embryonic stem (ES) cells. Chimeric males were bred with CD1 females to establish the colony. The Gtf2i^3'UTRloxP mice were bred at least ten generations with CD1, and then used as described below.

The XS0608 allele (Gtf2ird1^{Gt(XS0608)Wtsi}) has a loxP site inserted into intron 4 of the general transcription factor II I repeat domain-containing 1 locus (Gtf2ird1) on chromosome 5. First, the pGT0lxf gene trap vector was obtained containing (from 5' to 3') a mouse En2 intron 1, a lox71 site, a mouse En2 exon 2 splice acceptor, a loxp site, a β-geo fusion reporter protein (β-galactosidase and neomycin phosphotransferase), an SV40 polyadenylation sequence and a frt site. The vector was electroporated into 129P2/OlaHsd-derived E14TG2a.4 ES cells. ES cells with the gene trap vector randomly inserted into Gtf2ird1 intron 4 were identified and named line XS0608. Chimeric males were bred with CD1 females to establish the colony. The XS0608 mice were bred at least five generations with CD1, and then used as described below.

To generate the Gtf2i^Dup allele (Dp(5Gtf2i-Gtf2ird1)1Lro), Dr. Osborne first bred CD1.Gtf2i^3'UTRloxP animals to mice expressing Cre recombinase during male meiosis (Sycp1-Cre transgenic mice bred more than ten generations on CD1; see Stock No. 003466). The CD1.Gtf2i^3'UTRloxP::Sycp1-Cre double mutant was then bred to CD1.XS0608 mice; producing the triple mutant (CD1.Gtf2i^3'UTRloxP::XS0608::Sycp1-Cre). Subsequent male germline recombination of the loxP sites produces some male gametes with a chromosome 5 composed of the centromeric sequences from the XS0608 allele, a single remaining loxP site, and then the telomeric sequences from the Gtf2i^3'UTRloxP allele; i.e., duplication of a functional Gtf2i gene and a non-functional Gtf2ird1 allele (see additional note below). Breeding to wildtype CD1 outbred females transmitted the Gtf2i^Dup allele to offspring.

Gtf2i^Dup mice were backcrossed nine generations with C57BL/6J inbred mice (the Cre transgene was removed and the Y chromosome was made C57BL/6J), and then sent to The Jackson Laboratory Repository in 2015. Upon arrival, males were used to cryopreserve sperm. To generate our living colony, an aliquot of the frozen sperm was used to fertilize oocytes from C57BL/6J inbred females (Stock No. 000664).

Additional note: the Gtf2i^3'UTRloxP-derived sequences that remain on the duplication region do not include the neo cassette. In addition, the XS0608-derived Gtf2ird1 sequences that remain on the duplication region (including the loxP::β-geo fusion::SV40pA::frt and downstream Gtf2ird1 coding exons) result in a null allele because the upstream Gtf2ird1 sequences and gene trap splice acceptor sequences are absent.

Control Suggestions

Noncarrier
000664 C57BL/6J

Additional Information

Considerations for Choosing Controls

Selected References

Mervis CB; Dida J; Lam E; Crawford-Zelli NA; Young EJ; Henderson DR; Onay T; Morris CA; Woodruff-Borden J; Yeomans J; Osborne LR. 2012. Duplication of GTF2I results in separation anxiety in mice and humans. Am J Hum Genet 90(6):1064-70PubMed: 22578324 MGI: J:196809

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Genetics

Dp(5Gtf2i-Gtf2ird1)1Lro

Allele Symbol: Dp(5Gtf2i-Gtf2ird1)1Lro

Allele Name	duplication, Chr 5, L Osborne 1
Allele Type	Targeted (Not Applicable)
Allele Synonym(s)	Dp(5Gtf2i-Gtf2ird1)1Lro; duplication, Chr 5, L Osborne 1
Gene Symbol and Name	Dp(5Gtf2i-Gtf2ird1)1Lro, duplication, Chr 5, L Osborne 1
Gene Synonym(s)	Dp(5Gtf2i-Gtf2ird)1Lro; Dp(5Gtf2i-Gtf2ird)1Lro
Strain of Origin	129
Chromosome	5
General Note	Gtf2ird1^{Gt(XS0608)Wtsi} was generated in the E14.1TGa.4 ES cell line, derived from 129P2/OlaHsd, and Gtf2i^tm1Lro was made in the R1 ES cell line, derived from (129X1/SvJ x 129S1/Sv)F1-Kitl⁺.
Molecular Note	Cre-mediated recombination between loxP sites in intron 4 of Gtf2ird1^{Gt(XS0608)Wtsi} and downstream of exon 34 of Gtf2i^tm1Lro produced a duplication of the intervening sequence. Western blot analysis confirmed increased expression of Gtf2i but not Gtf2ird1 in the brain.

Disease/Phenotype

Disease Terms

Research Areas By Genotype

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

Developmental Biology Research
- Neurodevelopmental Defects
Neurobiology Research
- Neurodevelopmental Defects
  - Autism
- Behavioral and Learning Defects
  - high anxiety
- Channel and Transporter Defects
  - calcium
- Cortical Defects
Cell Biology Research
- Channel and Transporter Defects
  - calcium

Mammalian Phenotype Terms by Genotype

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

Genotype: Dp(5Gtf2i-Gtf2ird1)1Lro/Dp(5Gtf2i-Gtf2ird1)1Lro
involves: 129P2/OlaHsd * C57BL/6 * DBA/2

behavior/neurological phenotype

abnormal vocalization
- Normal - however, vocalizations decline over time of separation
- more ultrasonic vocalizations than in wild-type mice or Gtf2i^{Gt(YTA365)Byg} heterozygotes during maternal separation period

Genotype: Dp(5Gtf2i-Gtf2ird1)1Lro/+
involves: 129P2/OlaHsd * C57BL/6 * DBA/2

behavior/neurological phenotype

abnormal vocalization
- Normal - however, vocalizations decline over time of separation
- more ultrasonic vocalizations than in wild-type mice or Gtf2i^{Gt(YTA365)Byg} heterozygotes during maternal separation period

References

Mervis CB; Dida J; Lam E; Crawford-Zelli NA; Young EJ; Henderson DR; Onay T; Morris CA; Woodruff-Borden J; Yeomans J; Osborne LR. 2012. Duplication of GTF2I results in separation anxiety in mice and humans. Am J Hum Genet 90(6):1064-70PubMed: 22578324 MGI: J:196809

Additional - Dp(5Gtf2i-Gtf2ird1)1Lro related

Technical Support

Contact Technical Support

Genotyping Protocols
- High Resolution Melting: Dp(5Gtf2i-Gtf2ird1)1Lro-Alternate 1
- Genotyping resources and troubleshooting
Breeding Considerations

When maintaining our live colony, wildtype (noncarrier) females from the colony or C57BL/6J inbred females (Stock No. 000664) may be bred with hemizygous (Gtf2i^Dup/+) males.

Of note, the donating investigator reports hemizygous and homozygous mice are viable and fertile with healthy nutritional status. When maintaining their colony by breeding wildtype (noncarrier) females with hemizygous males, they report the mice are good breeders with no reduced survival.
- Additional Breeding and Husbandry Support
Mating System
- Noncarrier x Hemizygote
Citation
When using the Gtf2i duplication (Gtf2i^Dup) mouse strain in a publication, please cite the originating article(s) and include JAX stock #027792 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

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Live Mouse

Age

Genotype

Price

weeks

Cryorecovery - Pricing

Service	Genotype	Price
	Heterozygous or wildtype for Dp(5Gtf2i-Gtf2ird1)1Lro

We will fulfill your order by providing at least two carriers for each strain ordered. The total number, sex, and genotypes provided will vary, although typically 8 or more animals are provided. Please check genotypes which will be recovered. While the genotypes of all animals produced will be communicated to you prior to scheduling shipment, the genotypes of animals provided may not reflect the mating scheme and genotypes described in the strain description. Animals are typically ready to ship in 11-14 weeks. If a second recovery is required to produce the minimum number of animals, then delivery time would increase to approximately 25 weeks. If we fail to produce animals of the correct genotype, you will not be charged. We cannot guarantee the reproductive success of mice shipped to your facility. If the mice are lost after the first three days (post-arrival) or do not produce progeny at your facility, a new order and fee will be necessary.

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Also Known As: Gtf2i duplication (Gtf2iDup)

Donating Investigator

Genetic overview

Research Applications

Base Price

Detailed Description

Development

Control Suggestions

Additional Information

Selected References

Dp(5Gtf2i-Gtf2ird1)1Lro

Allele Symbol: Dp(5Gtf2i-Gtf2ird1)1Lro

Disease Terms

Research Areas By Genotype

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

Mammalian Phenotype Terms by Genotype

Genotype: Dp(5Gtf2i-Gtf2ird1)1Lro/Dp(5Gtf2i-Gtf2ird1)1Lroinvolves: 129P2/OlaHsd * C57BL/6 * DBA/2

behavior/neurological phenotype

Genotype: Dp(5Gtf2i-Gtf2ird1)1Lro/+involves: 129P2/OlaHsd * C57BL/6 * DBA/2

behavior/neurological phenotype

References

Additional - Dp(5Gtf2i-Gtf2ird1)1Lro 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

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

Also Known As: Gtf2i duplication (Gtf2i^Dup)

Genotype: Dp(5Gtf2i-Gtf2ird1)1Lro/Dp(5Gtf2i-Gtf2ird1)1Lro
involves: 129P2/OlaHsd * C57BL/6 * DBA/2

Genotype: Dp(5Gtf2i-Gtf2ird1)1Lro/+
involves: 129P2/OlaHsd * C57BL/6 * DBA/2