Overview

This CBP^deltaCH1 mutant strain carries a deletion mutation in the exon encoding the CH1 domain of the Crebbp gene, resulting in the disruption in the ability of the CREB binding protein to bind transcriptional regulators. This strain may be useful in studies of transcriptional regulation and Autism Spectrum Disorders.

Donating Investigator

Paul K. Brindle, St. Jude Children's Research Hospital

Genetic overview

Genetic Background	Generation

Crebbp^tm2Pkb

Allele Type	Gene Symbol	Gene Name
Targeted (Null/Knockout)	Crebbp	CREB binding protein

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Research Applications

Developmental Biology Research
Diabetes and Obesity Research
Neurobiology Research

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Base Price

Starting at:

$2,854.50 Domestic price Cryo Recovery

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Details

Detailed Description

The Crebbp gene encodes the CREB binding protein and the Ep300 gene encodes the E1A binding protein p300, both of which are highly conserved coactivators that promote transcription and are important to the function of many hematopoietic transcription factors. These CBP^deltaCH1 mutant mice carry an in-frame 52 amino acid deletion within the conserved 88 residue CH1 domain of the Crebbp gene. This mutation disrupts the ability of the CREB binding protein to bind transcriptional regulators. On the C57BL/6 congenic backgrounds homozygotes die after birth. Heterozygotes are viable and fertile on the C57BL/6 congenic background. Homozygotes on the C57BL/6 X 129 F1 hybrid background exhibit smaller size, moderate craniofacial anomalies (blunt snout), improved glucose tolerance and insulin sensitivity, as well as repetitive forelimb rubbing (limb grasping) & repetitive grooming behavior, hyperactivity and reduced anxiety. The F1 hybrids are models for Rubinstein-Taybi Syndrome and Autism Spectrum Disorders. RT-PCR confirms the correct splicing of the RNA (that would produce the deletion in the CH1 domain) in mutant MEFs. Expression of the mutant protein is similar to wild type protein when compared between wild type and homozygous mutant MEFs.

Development

A targeting vector containing a loxP site flanked NEO selection cassette was utilized in the construction of this mutant. This selection cassette was inserted upstream of the CH1 domain encoding exons and the in-frame 52 amino acid deletion (amino acids 342-393) within the conserved 88 residue CH1 domain encoding exon. The construct was electroporated into 129P2/OlaHsd derived E14 embryonic stem (ES) cells which were transiently transfected with a Cre recombinase vector to remove the selection cassette. ES cells that had successfully undergone Cre-mediated recombination and no longer retained the cassette were injected into blastocysts. The resulting chimeric animals were tested for germline transmission. The mice were then backcrossed to C57BL/6J for 24 generations, with female heterozygotes backcrossed to wildtype C57BL/6J males at N3. Upon arrival at The Jackson Laboratory, the mice were crossed to C57BL/6J (Stock No. 000664) at least once to establish the colony.

Control Suggestions

Wild-type siblings from the colony

Additional Information

Considerations for Choosing Controls

Selected References

Kasper LH; Boussouar F; Boyd K; Xu W; Biesen M; Rehg J; Baudino TA; Cleveland JL; Brindle PK. 2005. Two transactivation mechanisms cooperate for the bulk of HIF-1-responsive gene expression. EMBO J 24(22):3846-58PubMed: 16237459 MGI: J:103607

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Genetics

Crebbp^tm2Pkb

Allele Symbol: Crebbp^tm2Pkb

Allele Name	targeted mutation 2, Paul K Brindle
Allele Type	Targeted (Null/Knockout)
Allele Synonym(s)	CBP^deltaCH1
Gene Symbol and Name	Crebbp, CREB binding protein
Gene Synonym(s)
Strain of Origin	129P2/OlaHsd
Chromosome	16
Molecular Note	Portions of the CH1 domain (amino acids 342-393) was deleted and a neomycin resistance cassette flanked by loxp sites was introduced to the upstream intron. Transient infection of the ES cells with a Cre-expressing vector excised the neomycin cassette. RT-PCR confirmed the deletion in mutant MEFs.

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:

Developmental Biology Research
- Growth Defects
  - Growth Defects (homozygous)
- Perinatal Lethality
  - Homozygous
- Craniofacial and Palate Defects
Diabetes and Obesity Research
- Insulin Resistance
Neurobiology Research
- Behavioral and Learning 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: Crebbp^tm2Pkb/Crebbp^tm2Pkb
(B6.129P2-Crebbp/Pkb x 129S2.129P2(B6)-Crebbp/Pkb)F1

craniofacial phenotype

short nasal bone
- 100% penetrance of shortened nasal bones

flattened snout
- blunt snouts

abnormal occipital bone morphology
- E18.5 mutants show developmental defects in the occipital bone

supernumerary teeth
- partial penetrance of hyperdontia

growth/size/body region phenotype

decreased body size

flattened snout
- blunt snouts

supernumerary teeth
- partial penetrance of hyperdontia

mammalian phenotype

mortality/aging
- Normal - normal lifespan after weaning

nervous system phenotype

increased post-tetanic potentiation
- Normal - however, basal synaptic transmission and presynaptic function are intact
- post-tetanic potentiation at excitatory synapses between CA3 and CA1 pyramidal neurons is enhanced

skeleton phenotype

short nasal bone
- 100% penetrance of shortened nasal bones

split xiphoid process
- E18.5 mutants show bifurcation of the xyphoid process

abnormal occipital bone morphology
- E18.5 mutants show developmental defects in the occipital bone

supernumerary teeth
- partial penetrance of hyperdontia

behavior/neurological phenotype

impaired coordination
- although mutants show normal latency to fall from an accelerating rotard, when the rod is modified with tape to reduce surface friction, mutants fall sooner when they walk with, but not against, the direction of the rotating rod, suggesting impaired motor function

hyperactivity
- in the open-field test, mice travel father than wild-type mice, rear more frequently, and spend more time in the central zone, indicating hyperactivity

decreased anxiety-related response
- in the elevated-plus-maze experiments, mutants spend less time in the closed arm and enter the closed arm less frequently, indicating less anxiety

increased grooming behavior
- mice spend increased time self-grooming
- Normal - however, mice show a normal pain response in a hot plate assay

decreased grip strength
- in the wire hang assay, mice fall from the wire more quickly than controls and exhibit reduced grip strength

abnormal long term object recognition memory
- mice exhibit impaired long-term recognition memory but intact short-term memory

decreased aggression towards males
- in the resident-intruder paradigm, mice how much less aggression than wild-type males

abnormal social investigation
- mice spend less time interacting with a mouse introduced into the chamber and show reduced preference for a novel versus a familiar mouse, indicating impaired social interaction

increased vertical activity
- in the open-field test, mice rear more frequently

abnormal nest building behavior
- in the nesting behavior assay, mice show poor nest building abilities

increased stereotypic behavior
- mice exhibit stereotyped forelimb movements

Genotype: Crebbp^tm2Pkb/Crebbp^tm2Pkb
involves: 129P2/OlaHsd * C57BL/6

craniofacial phenotype

cleft secondary palate
- about 50% of homozygotes have cleft secondary palate

digestive/alimentary phenotype

cleft secondary palate
- about 50% of homozygotes have cleft secondary palate

growth/size/body region phenotype

cleft secondary palate
- about 50% of homozygotes have cleft secondary palate

mortality/aging

perinatal lethality, incomplete penetrance
- essentially all homozygotes die shortly after birth; one homozygote out of 651 total mice survived to adulthood but was runted; at E18.5 and P0.5, homozygotes are detected at near the expected ratio

respiratory system phenotype

abnormal lung interstitium morphology
- at E18.5 mutants have thickened interstitial septa

abnormal pulmonary alveolus morphology
- mutants have decreased alveolar airspaces

small lung
- on a mixed background, E18.5 homozygotes have smaller lungs than wild-type or homozygous Ep300^tm3Pkb mutants

Genotype: Crebbp^tm2Pkb/Crebbp⁺
involves: 129P2/OlaHsd * C57BL/6

mortality/aging

preweaning lethality, incomplete penetrance
- Normal - there is a decrease of ~30% in number of heterozygotes seen at adulthood compared to expected

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

Genotype: Crebbp^tm2Pkb/Crebbp^tm2Pkb
(B6.129-Crebbp x 129-Crebbp)F1

craniofacial phenotype

abnormal craniofacial morphology
- homozygotes that survive to maturity have craniofacial defects

growth/size/body region phenotype

postnatal growth retardation
- surviving homozygotes are growth retarded

mortality/aging

perinatal lethality, incomplete penetrance
- Background Sensitivity - about 25% of homozygotes survive to maturity on this background

References

Kasper LH; Boussouar F; Boyd K; Xu W; Biesen M; Rehg J; Baudino TA; Cleveland JL; Brindle PK. 2005. Two transactivation mechanisms cooperate for the bulk of HIF-1-responsive gene expression. EMBO J 24(22):3846-58PubMed: 16237459 MGI: J:103607

Additional - Crebbp^tm2Pkb related

Technical Support

CONTACT TECHNICAL SUPPORT

Genotyping Protocols
- Standard PCR:Crebbpalternate1
- Genotyping resources and troubleshooting
Breeding Considerations

When maintaining a live colony, heterozygous mice may be bred together, to wildtype siblings, or to C57BL/6J inbred mice (Stock No. 000664). Homozygotes have a perinatal lethal phenotype.
- Additional Breeding and Husbandry Support
Citation
When using the B6.129P2-Crebbp^tm2Pkb/J mouse strain in a publication, please cite the originating article(s) and include JAX stock #025172 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 Crebbp<tm2Pkb>

Payment Terms and Conditions

Terms are granted by individual review and stated on the customer invoice(s) and account statement. These transactions are payable in U.S. currency within the granted terms. Payment for services, products, shipping containers, and shipping costs that are rendered are expected within the payment terms indicated on the invoice or stated by contract. Invoices and account balances in arrears of stated terms may result in The Jackson Laboratory pursuing collection activities including but not limited to outside agencies and court filings.

The Jackson Laboratory's Genotype Promise

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.

Terms Of Use

General Terms and Conditions

Questions about Terms of Use

Additional Use Restrictions Apply

Use of MICE by companies or for-profit entities requires a license prior to shipping.

Licensing Information

Phone: 207-288-6470

Email: TechTran@jax.org

Donating Investigator

Genetic overview

Research Applications

Base Price

Detailed Description

Development

Control Suggestions

Additional Information

Selected References

Crebbptm2Pkb

Allele Symbol: Crebbptm2Pkb

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: Crebbptm2Pkb/Crebbptm2Pkb(B6.129P2-Crebbp/Pkb x 129S2.129P2(B6)-Crebbp/Pkb)F1

craniofacial phenotype

growth/size/body region phenotype

mammalian phenotype

nervous system phenotype

skeleton phenotype

behavior/neurological phenotype

Genotype: Crebbptm2Pkb/Crebbptm2Pkbinvolves: 129P2/OlaHsd * C57BL/6

craniofacial phenotype

digestive/alimentary phenotype

growth/size/body region phenotype

mortality/aging

respiratory system phenotype

Genotype: Crebbptm2Pkb/Crebbp+involves: 129P2/OlaHsd * C57BL/6

mortality/aging

Genotype: Crebbptm2Pkb/Crebbptm2Pkb(B6.129-Crebbp x 129-Crebbp)F1

craniofacial phenotype

growth/size/body region phenotype

mortality/aging

References

Additional - Crebbptm2Pkb 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

Payment Terms and Conditions

The Jackson Laboratory's Genotype Promise

Terms Of Use

Additional Use Restrictions Apply

Licensing Information

Crebbp^tm2Pkb

Allele Symbol: Crebbp^tm2Pkb

Genotype: Crebbp^tm2Pkb/Crebbp^tm2Pkb
(B6.129P2-Crebbp/Pkb x 129S2.129P2(B6)-Crebbp/Pkb)F1

Genotype: Crebbp^tm2Pkb/Crebbp^tm2Pkb
involves: 129P2/OlaHsd * C57BL/6

Genotype: Crebbp^tm2Pkb/Crebbp⁺
involves: 129P2/OlaHsd * C57BL/6

Genotype: Crebbp^tm2Pkb/Crebbp^tm2Pkb
(B6.129-Crebbp x 129-Crebbp)F1

Additional - Crebbp^tm2Pkb related