Overview

Also Known As:p27-

Homozygous mice of the cyclin-dependent kinase inhibitor 1B (Cdkn1b) knock-out (also referred to as p27^kip ) exhibit multi-organ hyperplasia and develop pituitary tumors. These mice may be useful in studies of tumorigenesis.

Donating Investigator

Dr. Matthew Fero, Fred Hutchinson Cancer Research Center

Genetic overview

Genetic Background	Generation
000664 C57BL/6J

Cdkn1b^tm1Mlf

Allele Type	Gene Symbol	Gene Name
Targeted (Null/Knockout)	Cdkn1b	cyclin-dependent kinase inhibitor 1B

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Research Applications

Cancer Research
Reproductive Biology 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

Mice deficient in p27^kip are viable and larger than normal littermates, with increased cellularity of all tissues. The thymus and spleen are particularly enlarged. Homozygous (nullizygous) adult mice have a shortened lifespan due to the growth of benign intermediate lobe pituitary tumors. Female mice are infertile, with a follicular phase ovulatory block. Large doses of exogenous gonadotropin induce ovulation, but both implantation and intrauterine embryonic development is impaired. The mice demonstrate haploid-insufficient susceptibility to the development of adenomas in the pituitary, intestine and lung adenomas following exposure to gamma irradiation or chemical carcinogens.

Development

This strain was generated by Dr. Matthew Fero at the Fred Hutchinson Cancer Research Center. The targeting construct contains a neo resistance gene and replaces the entire coding region of the Cdkn1b gene. 129S4/SvJaeSor-derived AK7 ES cells were used and the mutation was subsequently backcrossed to C57BL/6 mice.

Control Suggestions

Wild-type from the colony
000664 C57BL/6J

Additional Information

Considerations for Choosing Controls

Selected References

Fero ML; Rivkin M; Tasch M; Porter P; Carow CE; Firpo E; Polyak K; Tsai LH; Broudy V; Perlmutter RM; Kaushansky K; Roberts JM. 1996. A syndrome of multiorgan hyperplasia with features of gigantism, tumorigenesis, and female sterility in p27(Kip1)-deficient mice. Cell 85(5):733-44PubMed: 8646781 MGI: J:33400

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Genetics

Cdkn1b^tm1Mlf

Allele Symbol: Cdkn1b^tm1Mlf

Allele Name	targeted mutation 1, Matthew Fero
Allele Type	Targeted (Null/Knockout)
Allele Synonym(s)	Cdkln1^btm1Mlf; p27-; p27^Kip1; p27^Kip1-; p27^kip1-null
Gene Symbol and Name	Cdkn1b, cyclin-dependent kinase inhibitor 1B
Gene Synonym(s)
Strain of Origin	129S4/SvJaeSor
Chromosome	6
Molecular Note	Replacement of the entire coding region of the Cdkn1b gene with a neomycin cassette.
Mutations Made By	Dr. Matthew Fero, Fred Hutchinson Cancer Research Center

Disease/Phenotype

Disease Terms

Research Areas By Phenotype

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

Cancer Research
- Increased Tumor Incidence
  - Adenomas: multiple tissues - induced
  - Adenomas

Genotype: Cdkn1b^tm1Mlf related

Cancer Research
- Genes Regulating Growth and Proliferation
Reproductive Biology Research
- Fertility Defects
  - females only
Cell Biology Research
- Genes Regulating Growth and Proliferation

Mammalian Phenotype Terms by Genotype

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

Genotype: Cdkn1b^tm1Mlf/Cdkn1b^tm1Mlf
involves: 129S4/SvJaeSor * C57BL/6NHsd

cellular phenotype

abnormal cell proliferation
- at E16, anti-PCNA staining of the organ of Corti indicates that proliferation of sensory cell progenitors abnormally continues after E14 (i.e. past the normal time of cell cycle withdrawal), leading to the appearance of supernumerary hair cells and supporting cells in mutant mice
- at P6, PCNA-positive cells are no longer seen in Deiters' cell region as they are at E16, but appear in clusters in the region of Hensen's cells, lateral to the outermost row of OHCs, as well as in the pillar cell regions separating IHCs and OHCs
- at E16, PCNA-positive cells are observed in the Deiters' cell region beneath the newly differentiated hair cells stained with anti-myosin VIIa
- ting cells in mutant mice

mammalian phenotype

behavior/neurological phenotype
- Normal - no obvious behavioral defects related to vestibular function, such as circling or balance deficits, are observed

nervous system phenotype

increased cochlear inner hair cell number
- in homozygotes, IHC numbers are increased by a mean of 23% relative to wild-type mice
- at P6, the mutant inner row contains a partly disorganized line of at most two hair cells, whereas wild-type mice normally contain a single row of inner hair cells

increased cochlear outer hair cell number
- in homozygotes, OHC numbers are increased by a mean of 36% relative to wild-type mice
- at P6, homozygotes contain four, partly disorganized, rows of cochlear outer hair cells (OHCs) instead of the expected three rows of OHCs seen in wild-type mice

increased cochlear hair cell number
- homozygotes develop supernumerary hair cells in both the inner and outer rows of hair cells

growth/size/body region phenotype

increased body size
- homozygotes are larger than wild-type littermates as a result of multiorgan hyperplasia

hearing/vestibular/ear phenotype

abnormal organ of Corti morphology
- continued presence of proliferating cells in the postnatal organ of Corti, as well as abnormal persistence of Cdkn1b expression in mature supporting cells indicate a role for Cdkn1b in maintaining these cells in a quiescent state
- at P6, homozygotes exhibit hyperplasia of the organ of Corti

increased cochlear inner hair cell number
- in homozygotes, IHC numbers are increased by a mean of 23% relative to wild-type mice
- at P6, the mutant inner row contains a partly disorganized line of at most two hair cells, whereas wild-type mice normally contain a single row of inner hair cells

increased or absent threshold for auditory brainstem response
- at 10 weeks of age, homozygotes display a significantly elevated mean, click-evoked, ABR threshold (77 db SPL) relative to age-matched wild-type mice (20 db SPL)

abnormal pillar cell morphology
- at P6, homozygotes display supernumerary cells in the pillar cell region of the organ of Corti, where normally one inner pillar and one outer pillar cells are present in wild-type mice

increased organ of Corti supporting cell number
- homozygotes develop an excess number of supporting cells, including pillar cells, separating IHCs from OHCs and occupying the area of the tunnel of Corti

impaired hearing
- at 10 weeks of age, homozygotes are severely hearing-impaired

increased cochlear outer hair cell number
- at P6, homozygotes contain four, partly disorganized, rows of cochlear outer hair cells (OHCs) instead of the expected three rows of OHCs seen in wild-type mice
- in homozygotes, OHC numbers are increased by a mean of 36% relative to wild-type mice

increased cochlear hair cell number
- homozygotes develop supernumerary hair cells in both the inner and outer rows of hair cells

Genotype: Cdkn1b^tm1Mlf/Cdkn1b^tm1Mlf
involves: 129S4/SvJaeSor * C57BL/6J

cellular phenotype

increased T cell proliferation
- thymoblasts and splenic T cells have an increase in percentage of S phase cells and a 3-4-fold increase in cyclin E-associated kinase activity, indicating increased cell proliferation

growth/size/body region phenotype

increased body weight
- body weight increase becomes evident between 2-3 weeks of age, is maximal by 10 weeks of age, and is maintained throughout adulthood and is partly attributable to enlargement of all internal organs, however do not have an increase in body fat amount

spleen hyperplasia
- becomes evident by 4 weeks of age

enlarged spleen
- disproportionately enlarged

hematopoietic system phenotype

spleen hyperplasia
- becomes evident by 4 weeks of age

thymus hyperplasia
- 3-fold increase in the number of thymocytes, however development of thymocytes is normal
- becomes evident by 4 weeks of age

abnormal definitive hematopoiesis
- increase in the number of granulocyte-macrophage, early and late erythroid progenitors, and megakaryotic progenitors in both the marrow and spleen

enlarged spleen
- disproportionately enlarged

enlarged thymus
- disproportionately enlarged

abnormal spleen morphology

abnormal thymus morphology

increased T cell proliferation
- thymoblasts and splenic T cells have an increase in percentage of S phase cells and a 3-4-fold increase in cyclin E-associated kinase activity, indicating increased cell proliferation

immune system phenotype

thymus hyperplasia
- becomes evident by 4 weeks of age
- 3-fold increase in the number of thymocytes, however development of thymocytes is normal

abnormal spleen morphology

enlarged thymus
- disproportionately enlarged

increased T cell proliferation
- thymoblasts and splenic T cells have an increase in percentage of S phase cells and a 3-4-fold increase in cyclin E-associated kinase activity, indicating increased cell proliferation

spleen hyperplasia
- becomes evident by 4 weeks of age

enlarged spleen
- disproportionately enlarged

abnormal thymus morphology

liver/biliary system phenotype

abnormal hepatocyte morphology
- average of 23% increase in hepatocyte cell density

mortality/aging

premature death
- Background Sensitivity - no indication of early mortality at 9 months of age on the mixed 129/Sv and C57BL/6J background, however on a 129/Sv background, majority die with massively enlarged pituitary tumors

neoplasm

increased pituitary adenoma incidence
- adenomatous, neoplastic transformation of the pars intermedia

nervous system phenotype

enlarged pituitary gland
- disproportionately enlarged

abnormal cerebral cortex morphology
- about 30% increase in neuronal cell density in the cerebral cortex

abnormal epithalamus morphology
- about 30% increase in neuronal cell density in the habenular nucleus

pituitary gland hyperplasia
- gross hyperplasia becomes evident at 8-10 weeks of age

abnormal hippocampus morphology
- about 30% increase in neuronal cell density in the hippocampus

increased pituitary adenoma incidence
- adenomatous, neoplastic transformation of the pars intermedia

reproductive system phenotype

absent corpus luteum
- secondary ovarian follicles develop but do not progress to form corpora lutea

female infertility
- females do not become pregnant, however, exogenous administration of gonadotropins induced ovulation, differentiation of the corpora lutea, and early development of viable embryos, with embryos implanting but not developing to term

endocrine/exocrine gland phenotype

enlarged pituitary gland
- disproportionately enlarged

increased pituitary adenoma incidence
- adenomatous, neoplastic transformation of the pars intermedia

pituitary gland hyperplasia
- gross hyperplasia becomes evident at 8-10 weeks of age

thymus hyperplasia
- becomes evident by 4 weeks of age
- 3-fold increase in the number of thymocytes, however development of thymocytes is normal

absent corpus luteum
- secondary ovarian follicles develop but do not progress to form corpora lutea

abnormal thymus morphology

enlarged thymus
- disproportionately enlarged

vision/eye phenotype

abnormal retinal neuronal layer morphology
- loss of the normally sharp boundary between the inner and outer nuclear layer

disorganized retinal layers
- subtle disorganization of the retina

Genotype: Cdkn1b^tm1Mlf/Cdkn1b^tm1Mlf
involves: 129S4/SvJaeSor

cellular phenotype

abnormal neuron differentiation
- cortex of mutant shows fewer neurons born on E14.5 that express differentiation markers at E17.5
- reduction in differentiation is most prominent in VZ/SVZ

abnormal neuronal migration
- defect in cortical neuronal migration is observed at E17.5; fewer cells reach the cortical plate in mutants compared to wild-type
- greater numbers of cells accumulates in the ventricular zone (VZ) and subventricular zone (SVZ) in mutants
- radial migration is impaired in mutant cortices

homeostasis/metabolism phenotype

increased incidence of tumors by chemical induction
- increase in incidence of urethane-induced lung tumors compared to wild-type, with more large tumors than in heterozygotes
- 100% penetrance of pituitary adenomas and harderian gland tumors after 20 weeks of urethane treatment, as well as increased incidence of liver hemangiomas, uterine tumors and ovarian granulose cell tumors

immune system phenotype

enlarged spleen
- spleens are enlarged when recipients receive bone marrow cells from wild-type or mutant donors

enlarged thymus
- Cdkn1b-deficient mice develop hyperplastic thymuses when receiving bone marrow from wild-type or mutant donors

spleen hypoplasia
- Cdkn1b-deficient mice show hypercellular spleens when receiving transplants of bone marrow from mutant or wild-type mice

neoplasm

increased incidence of tumors by chemical induction
- 100% penetrance of pituitary adenomas and harderian gland tumors after 20 weeks of urethane treatment, as well as increased incidence of liver hemangiomas, uterine tumors and ovarian granulose cell tumors
- increase in incidence of urethane-induced lung tumors compared to wild-type, with more large tumors than in heterozygotes

nervous system phenotype

abnormal neuron differentiation
- cortex of mutant shows fewer neurons born on E14.5 that express differentiation markers at E17.5
- reduction in differentiation is most prominent in VZ/SVZ

abnormal neuronal migration
- defect in cortical neuronal migration is observed at E17.5; fewer cells reach the cortical plate in mutants compared to wild-type
- greater numbers of cells accumulates in the ventricular zone (VZ) and subventricular zone (SVZ) in mutants
- radial migration is impaired in mutant cortices

endocrine/exocrine gland phenotype

enlarged thymus
- Cdkn1b-deficient mice develop hyperplastic thymuses when receiving bone marrow from wild-type or mutant donors

growth/size/body region phenotype

enlarged spleen
- spleens are enlarged when recipients receive bone marrow cells from wild-type or mutant donors

hematopoietic system phenotype

enlarged spleen
- spleens are enlarged when recipients receive bone marrow cells from wild-type or mutant donors

enlarged thymus
- Cdkn1b-deficient mice develop hyperplastic thymuses when receiving bone marrow from wild-type or mutant donors

spleen hypoplasia
- Cdkn1b-deficient mice show hypercellular spleens when receiving transplants of bone marrow from mutant or wild-type mice

Genotype: Cdkn1b^tm1Mlf/Cdkn1b⁺
involves: 129S4/SvJaeSor

homeostasis/metabolism phenotype

increased incidence of tumors by chemical induction
- increased incidence of liver hemangiomas, uterine tumors, and ovarian granulose cell tumors after 20 weeks of urethane treatment, but less than in homozygotes
- similar increase in the incidence of urethane-induced lung tumors as homozygotes, with more large tumors than in wild-type

neoplasm

increased incidence of tumors by chemical induction
- increased incidence of liver hemangiomas, uterine tumors, and ovarian granulose cell tumors after 20 weeks of urethane treatment, but less than in homozygotes
- similar increase in the incidence of urethane-induced lung tumors as homozygotes, with more large tumors than in wild-type

Genotype: Cdkn1b^tm1Mlf/Cdkn1b⁺
involves: 129S4/SvJaeSor * C57BL/6NHsd

hearing/vestibular/ear phenotype

increased cochlear inner hair cell number
- at P6, heterozygotes display occasional supernumerary inner hair cells throughout the organ of Corti; never observed in wild-type mice
- Normal - in contrast, the heterozygous outer hair cell population remains normal relative to wild-type mice

nervous system phenotype

increased cochlear inner hair cell number
- at P6, heterozygotes display occasional supernumerary inner hair cells throughout the organ of Corti; never observed in wild-type mice
- Normal - in contrast, the heterozygous outer hair cell population remains normal relative to wild-type mice

References

Fero ML; Rivkin M; Tasch M; Porter P; Carow CE; Firpo E; Polyak K; Tsai LH; Broudy V; Perlmutter RM; Kaushansky K; Roberts JM. 1996. A syndrome of multiorgan hyperplasia with features of gigantism, tumorigenesis, and female sterility in p27(Kip1)-deficient mice. Cell 85(5):733-44PubMed: 8646781 MGI: J:33400

Additional References

Verdoodt B; Blazek T; Rauch P; Schuler G; Steinkasserer A; Lutz MB; Funk JO. 2003. The cyclin-dependent kinase inhibitors p27Kip1 and p21Cip1 are not essential in T cell anergy. Eur J Immunol 33(11):3154-63PubMed: 14579284 MGI: J:86442

Additional - Cdkn1b^tm1Mlf related

Technical Support

CONTACT TECHNICAL SUPPORT

Genotyping Protocols
- Standard PCR:Cdkn1b
- Standard PCR:Generic Neo
- Standard PCR:Cdkn1b
- Standard PCR:Cdkn1b Alternate3
- Probe:Generic Neo
- Genotyping resources and troubleshooting
Breeding Considerations

Homozygote males are fertile, but homozygote females are not. Colony currently maintained by heterozygote X heterozygote matings. Coat color from breeding: Black
- Additional Breeding and Husbandry Support
Appearance
- black
  Related Genotype: a/a
Citation
When using the p27- mouse strain in a publication, please cite the originating article(s) and include JAX stock #002781 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 Wild-type for Cdkn1b<tm1Mlf>

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

Licensing Information

Phone: 207-288-6470

Email: TechTran@jax.org

Also Known As:p27-

Donating Investigator

Genetic overview

Research Applications

Base Price

Detailed Description

Development

Control Suggestions

Additional Information

Selected References

Cdkn1btm1Mlf

Allele Symbol: Cdkn1btm1Mlf

Disease Terms

Research Areas By Phenotype

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

Genotype: Cdkn1btm1Mlf related

Mammalian Phenotype Terms by Genotype

Genotype: Cdkn1btm1Mlf/Cdkn1btm1Mlfinvolves: 129S4/SvJaeSor * C57BL/6NHsd

cellular phenotype

mammalian phenotype

nervous system phenotype

growth/size/body region phenotype

hearing/vestibular/ear phenotype

Genotype: Cdkn1btm1Mlf/Cdkn1btm1Mlfinvolves: 129S4/SvJaeSor * C57BL/6J

cellular phenotype

growth/size/body region phenotype

hematopoietic system phenotype

immune system phenotype

liver/biliary system phenotype

mortality/aging

neoplasm

nervous system phenotype

reproductive system phenotype

endocrine/exocrine gland phenotype

vision/eye phenotype

Genotype: Cdkn1btm1Mlf/Cdkn1btm1Mlfinvolves: 129S4/SvJaeSor

cellular phenotype

homeostasis/metabolism phenotype

immune system phenotype

neoplasm

nervous system phenotype

endocrine/exocrine gland phenotype

growth/size/body region phenotype

hematopoietic system phenotype

Genotype: Cdkn1btm1Mlf/Cdkn1b+involves: 129S4/SvJaeSor

homeostasis/metabolism phenotype

neoplasm

Genotype: Cdkn1btm1Mlf/Cdkn1b+involves: 129S4/SvJaeSor * C57BL/6NHsd

hearing/vestibular/ear phenotype

nervous system phenotype

References

Additional References

Additional - Cdkn1btm1Mlf related

Genotyping Protocols

Breeding Considerations

Appearance

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

Licensing Information

Cdkn1b^tm1Mlf

Allele Symbol: Cdkn1b^tm1Mlf

Genotype: Cdkn1b^tm1Mlf related

Genotype: Cdkn1b^tm1Mlf/Cdkn1b^tm1Mlf
involves: 129S4/SvJaeSor * C57BL/6NHsd

Genotype: Cdkn1b^tm1Mlf/Cdkn1b^tm1Mlf
involves: 129S4/SvJaeSor * C57BL/6J

Genotype: Cdkn1b^tm1Mlf/Cdkn1b^tm1Mlf
involves: 129S4/SvJaeSor

Genotype: Cdkn1b^tm1Mlf/Cdkn1b⁺
involves: 129S4/SvJaeSor

Genotype: Cdkn1b^tm1Mlf/Cdkn1b⁺
involves: 129S4/SvJaeSor * C57BL/6NHsd

Additional - Cdkn1b^tm1Mlf related