Overview

Also Known As:Akap12^-/-;Rb^PE-/-

This strain has been discontinued. Please search the JAX Mice database for other strains which may be suitable for your studies. Single strains are available as follows: Stock No. 026662 STOCK Tg(Pbsn-cre)4Prb/J; Stock No. 026563 STOCK Rb1^tm2Brn/J; Stock No. 026228 STOCK Akap12^tm1Ihg/J

Akap12^-/-;Rb^PE-/- mice develop prostatic intraepithelial neoplasia by 2 months of age and are a model for early prostate intraepithelial neoplasia metastasis to lymph nodes.

Donating Investigator

Irwin H. Gelman, Roswell Park Cancer Institute

Genetic overview

Genetic Background	Generation

Rb1^tm2Brn

Allele Type	Gene Symbol	Gene Name
Targeted (Conditional ready (e.g. floxed), No functional change)	Rb1	RB transcriptional corepressor 1

Tg(Pbsn-cre)4Prb

Allele Type
Transgenic (Recombinase-expressing)

Akap12^tm1Ihg

Allele Type	Gene Symbol	Gene Name
Targeted (Null/Knockout)	Akap12	A kinase (PRKA) anchor protein (gravin) 12

View Genetics

Research Applications

Internal/Organ Research
Cancer Research

View All Research Applications

Details

Detailed Description

These mutant mice carry a knock-out allele for Akap12 and prostate epithelium specific deletion of Rb1. In human prostate cancer, AKAP12 and RB1 are downregulated.
Mice that are homozygous for the Akap12^tm1Ihg allele, homozygous for the Rb1^tm2Brn allele, and hemizygous for the Tg(Pbsn-cre)4Prb transgene, develop low grade prostatic intraepithelial neoplasia (PIN) in all prostate lobes by 2 months of age. By 5 months of age, 29% of these mice develop high-grade PIN. No adenocarcinoma is detected in mutant mice up to 24 months of age. 83% of mice exhibiting focal high-grade PIN lesions develop pelvic or inguinal lymph node metastases. Mice that are heterozygous for the Akap12^tm1Ihg allele, homozygous for the Rb1^tm2Brn allele, and hemizygous for the Tg(Pbsn-cre)4Prb transgene, are viable and fertile. 3-4% of single mutant mice homozygous for the Akap12^tm1Ihg allele die spontaneously as early as 4 months of age, and 10-25% of Akap12^tm1Ihg homozygotes are infertile or show delayed fertility (the Donating Investigator reports that breeding pairs may need to be housed for up to 3 weeks). To maintain prostate specific cre recombination, the Tg(Pbsn-cre)4Prb transgene must be inherited from the male only.

Development

These triple mutant mice were generated by crossing double mutant mice carrying the Rb1^tm2Brn allele and Tg(Pbsn-cre)4Prb transgene to mice carrying the
Akap12^tm1Ihg allele.

For the Akap12^tm1Ihg allele: a targeting vector containing a lacZ-NEO cassette was used to disrupt exon 2 of the targeted gene. The construct was electroporated into 129S4/SvJae derived J1 embryonic stem (ES) cells. Correctly targeted ES cells were injected into 129SvJ blastocysts. The resulting chimeric animals were tested for germline transmission. The mice were then backcrossed onto the C57BL/6 background for 6 generations. During backcrossing, the Y chromosome may not have been fixed to the C57BL/6 genetic background.

For the Rb1^tm2Brn allele: a targeting vector, designed by Dr. Anton Berns (The Netherlands Cancer Institute), was used to introduce loxP sites flanking exon 19 of the targeted gene. The construct was electroporated into unspecified 129 derived embryonic stem (ES) cells. Correctly targeted ES cells were injected into blastocysts. The resulting chimeric animals were tested for germline transmission. The mice were maintained on a mixed FVB;129 background.

For the Tg(Pbsn-cre)4Prb transgene: a transgenic construct, designed by Dr.Pradip Roy-Burman (University of Southern California), containing sequence encoding Cre recombinase under the control of the rat Pbsn, probasin, gene promoter with two tandem repeats of the androgen responsive region, was injected into fertilized (C57BL/6 x DBA/2)F1 mouse eggs. Founder line 1 was subsequently established and maintained on a mixed B6;D2 background.

Expression Data

Expressed Gene	cre, cre recombinase, bacteriophage P1
Site of Expression	Cre recombinase is expressed in the prostate epithelium.
Site of Expression

Control Suggestions

None Available

Additional Information

Considerations for Choosing Controls

Selected References

Akakura S; Huang C; Nelson PJ; Foster B; Gelman IH. 2008. Loss of the SSeCKS/Gravin/AKAP12 gene results in prostatic hyperplasia. Cancer Res 68(13):5096-103PubMed: 18593908 MGI: J:138882
Ko HK; Akakura S; Peresie J; Goodrich DW; Foster BA; Gelman IH. 2014. A transgenic mouse model for early prostate metastasis to lymph nodes. Cancer Res 74(3):945-53PubMed: 24492704 MGI: J:209148
Marino S; Vooijs M; van Der Gulden H; Jonkers J; Berns A. 2000. Induction of medulloblastomas in p53-null mutant mice by somatic inactivation of Rb in the external granular layer cells of the cerebellum. Genes Dev 14(8):994-1004PubMed: 10783170 MGI: J:61961
Wu X; Wu J; Huang J; Powell WC; Zhang J; Matusik RJ; Sangiorgi FO; Maxson RE; Sucov HM; Roy-Burman P. 2001. Generation of a prostate epithelial cell-specific Cre transgenic mouse model for tissue-specific gene ablation. Mech Dev 101(1-2):61-9PubMed: 11231059 MGI: J:68167
Zhou Z; Flesken-Nikitin A; Corney DC; Wang W; Goodrich DW; Roy-Burman P; Nikitin AY. 2006. Synergy of p53 and Rb Deficiency in a Conditional Mouse Model for Metastatic Prostate Cancer. Cancer Res 66(16):7889-98PubMed: 16912162 MGI: J:112104

View All References

Genetics

Rb1^tm2Brn

Allele Symbol: Rb1^tm2Brn

Allele Name	targeted mutation 2, Anton Berns
Allele Type	Targeted (Conditional ready (e.g. floxed), No functional change)
Allele Synonym(s)	flox19-RB1; pRb^L2; pRb^lox; Rb^f; Rb^F19; Rb^lox; Rb^LoxP
Gene Symbol and Name	Rb1, RB transcriptional corepressor 1
Gene Synonym(s)
Strain of Origin	129
Chromosome	14
General Note	Animals homozygous for the conditional floxed exon 19 allele did not show any tumor predisposition phenotype, and were of normal fertility. Phenotypic Similarity to Human Syndrome: Glucagonoma J:216559 in double homozygous Rb1 and Trp53 conditional mutants.
Molecular Note	LoxP sites flanking exon 19 were introduced to the gene by homologous recombination. The targeted allele was verified by Southern blot analysis.

Tg(Pbsn-cre)4Prb

Allele Symbol: Tg(Pbsn-cre)4Prb

Allele Name	transgene insertion 4, Pradip Roy-Burman
Allele Type	Transgenic (Recombinase-expressing)
Allele Synonym(s)	ARR2PB-Cre; PB-Cre; PbCre4; PB-Cre4
Gene Symbol and Name	Tg(Pbsn-cre)4Prb, transgene insertion 4, Pradip Roy-Burman
Gene Synonym(s)
Promoter	Pbsn, probasin, rat
Expressed Gene	cre, cre recombinase, bacteriophage P1
Site of Expression	Cre recombinase is expressed in the prostate epithelium.
Strain of Origin	(C57BL/6 x DBA/2)F1
Chromosome	UN
Molecular Note	The transgene is composed of the cre recombinase gene under the control of a composite promoter derived from rat Pbsn. The rat Pbsn promoter drives postnatal transgene expression in the prostatic epithelium. The transgene is expressed postnatally in prostatic epithelium with the highest level of expression in the lateral lobe of the prostate gland. A very low level of transgene expression was detected in the seminal vesicles, testes, and ovaries. No transgene expression was detected in any of the other tissue types examined.

Akap12^tm1Ihg

Allele Symbol: Akap12^tm1Ihg

Allele Name	targeted mutation 1, Irwin H Gelman
Allele Type	Targeted (Null/Knockout)
Allele Synonym(s)	mSSeCKS^-
Gene Symbol and Name	Akap12, A kinase (PRKA) anchor protein (gravin) 12
Gene Synonym(s)
Strain of Origin	129S4/SvJae
Chromosome	10
Molecular Note	A lacZ followed by a neomycin selection cassette were inserted in exon2. Western blot analysis demonstrated the absence of all three major isoforms (alpha, beta, gamma).

Disease/Phenotype

Disease Terms

Research Areas By Phenotype

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

Internal/Organ Research
- Prostate
Cancer Research
- Other
  - tumor metastasis

Mammalian Phenotype Terms by Genotype

References

Akakura S; Huang C; Nelson PJ; Foster B; Gelman IH. 2008. Loss of the SSeCKS/Gravin/AKAP12 gene results in prostatic hyperplasia. Cancer Res 68(13):5096-103PubMed: 18593908 MGI: J:138882
Ko HK; Akakura S; Peresie J; Goodrich DW; Foster BA; Gelman IH. 2014. A transgenic mouse model for early prostate metastasis to lymph nodes. Cancer Res 74(3):945-53PubMed: 24492704 MGI: J:209148
Marino S; Vooijs M; van Der Gulden H; Jonkers J; Berns A. 2000. Induction of medulloblastomas in p53-null mutant mice by somatic inactivation of Rb in the external granular layer cells of the cerebellum. Genes Dev 14(8):994-1004PubMed: 10783170 MGI: J:61961
Wu X; Wu J; Huang J; Powell WC; Zhang J; Matusik RJ; Sangiorgi FO; Maxson RE; Sucov HM; Roy-Burman P. 2001. Generation of a prostate epithelial cell-specific Cre transgenic mouse model for tissue-specific gene ablation. Mech Dev 101(1-2):61-9PubMed: 11231059 MGI: J:68167
Zhou Z; Flesken-Nikitin A; Corney DC; Wang W; Goodrich DW; Roy-Burman P; Nikitin AY. 2006. Synergy of p53 and Rb Deficiency in a Conditional Mouse Model for Metastatic Prostate Cancer. Cancer Res 66(16):7889-98PubMed: 16912162 MGI: J:112104

Additional - Akap12^tm1Ihg related

Additional - Rb1^tm2Brn related

Additional - Tg(Pbsn-cre)4Prb related

Technical Support

CONTACT TECHNICAL SUPPORT

Genotyping Protocols
- Standard PCR:Rb1 Alternate1
- Standard PCR:Akap12-Alternate 2
- Separated PCR:Rb1-Cre recombined
- Standard PCR:Generic Neo
- Standard PCR:Generic LacZ Melt Curve Analysis
- Standard PCR:Tg(Pbsn-cre)4Prb
- Probe:Generic Neo
- Probe:Generic LacZ Probe
- Probe:Rb1 Probe
- QPCR:Tg(Pbsn-cre)4Prb qPCR
- Genotyping resources and troubleshooting
Breeding Considerations

When maintaining a live colony, these mice can be bred as heterozygous for the Akap12^tm1Ihg allele, homozygous for the Rb1^tm2Brn allele, and hemizygous for the Tg(Pbsn-cre)4Prb transgene.

3-4% of single mutant mice homozygous for the Akap12^tm1Ihg allele die spontaneously as early as 4 months of age, and 10-25% of Akap12^tm1Ihg homozygotes are infertile or show delayed fertility requiring breeding pairs to be housed for up to 3 weeks. To maintain prostate specific cre recombination, the Tg(Pbsn-cre)4Prb transgene must be inherited from the male only.
- Additional Breeding and Husbandry Support
Mating System
- Wild Akap12tm1Ihg, Wild Rb1tm2Brn, Noncarrier Tg(Pbsn-cre)4Prb x Heterozygous Akap12tm1Ihg, Heterozygous Rb1tm2Brn, Hemizygous Tg(Pbsn-cre)4Pr

Terms Of Use

General Terms and Conditions

Questions about Terms of Use

Licensing Information

Phone: 207-288-6470

Email: TechTran@jax.org

Also Known As:Akap12-/-;RbPE-/-

Donating Investigator

Genetic overview

Research Applications

Detailed Description

Development

Expression Data

Control Suggestions

Additional Information

Selected References

Rb1tm2Brn

Allele Symbol: Rb1tm2Brn

Tg(Pbsn-cre)4Prb

Allele Symbol: Tg(Pbsn-cre)4Prb

Akap12tm1Ihg

Allele Symbol: Akap12tm1Ihg

Disease Terms

Research Areas By Phenotype

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

Mammalian Phenotype Terms by Genotype

References

Additional - Akap12tm1Ihg related

Additional - Rb1tm2Brn related

Additional - Tg(Pbsn-cre)4Prb related

Genotyping Protocols

Breeding Considerations

Mating System

Terms Of Use

Licensing Information

Also Known As:Akap12^-/-;Rb^PE-/-

Rb1^tm2Brn

Allele Symbol: Rb1^tm2Brn

Akap12^tm1Ihg

Allele Symbol: Akap12^tm1Ihg

Additional - Akap12^tm1Ihg related

Additional - Rb1^tm2Brn related