B6.129(D2)-Cdkn2c^tm1Yxi/LmoJ

Stock number: 029665
Product name: B6.p18 null , B6.p18-/-
Research areas: Cancer Research, Developmental Biology Research, Endocrine Deficiency Research, Hematological Research, Immunology, Inflammation and Autoimmunity Research, Internal/Organ Research, Research Tools, Virology Research

Description

Homozygous p18 knock-out mice exhibit widespread organomegaly, homeostatic expansion of B1a cells (but not of splenic conventional B cells), expansion of T cells, abnormal T cell physiology and increased pituitary adenoma incidence. These mice are useful for studies of cell cycle progression/regulation, tumorigenesis, B- and T-cell expansion and lupus.

Detailed description

Cyclin-dependent kinase inhibitors negatively regulate the cell cycle. The Cdkn2c gene encodes the cyclin-dependent kinase inhibitor p18^Ink4c, which is important in regulating B cell proliferation/differentiation, and is involved in cancer pathways. Cdkn2c contributes to lupus susceptibility by regulating the size of the B1a cell compartment and hence their contribution to autoimmunity (Cdkn2c is located within the Sle2c1 lupus susceptibility locus).

The p18 knock-out allele (p18-) expresses no CDKN2C protein in lysates derived from heart, kidney, lung, skeletal muscle or spleen. The donating investigator reports that homozygous mice on the C57BL/6J genetic background (B6.p18-/-) are viable and fertile, with the abnormalities described below.
Overall, p18-deficiency leads to widespread organomegaly, homeostatic expansion of B1a cells (but not of splenic conventional B cells), expansion of T cells, abnormal T cell physiology and increased pituitary adenoma incidence. By 2-3 weeks, p18-/- mice become distinctly larger than wildtype littermates with widespread organomegaly. Homozygous mice exhibit high incidence of pituitary gland hyperplastic or neoplastic progression (microscopically as early as 4 weeks of age) - with some p18-/- mice developing large pituitary adenomas by 9-13 months of age (grossly appear ataxic, thin and dehydrated). With the exception of pituitary tumors, no increased tumorigenesis is reported for p18-null mice (examined up to 13 months old).


Furthermore, B6.p18-deficiency partially contributes to the following B6.Sle2c1.Fas^lpr phenotypes: increased T cell activation characterized by the production of CD4-CD8- double negative T cells and activated memory T cells, as well as the concomitant decreased production of Foxp3+ regulatory T cells.

Of note, p18-/- mice on the BALB/c genetic background (BALBc.p18-/-) exhibit increased tumor spectrum, incidence and onset time in many tissues (including pituitary, thyroid, testis, pancreas and lung) compared to B6.p18-/- mice.

Development

The p18 knock-out allele was created by the laboratory of Dr. Yue Xiong (University of North Carolina at Chapel Hill) to replace exon 3 of the cyclin-dependent kinase inhibitor 2C [p18, inhibits CDK4] gene (Cdkn2c ; p18^Ink4c) on chromosome 4 with a neomycin resistance cassette. The construct was electroporated into 129/Sv-derived embryonic stem (ES) cells. Correctly targeted ES cells were injected into recipient blastocysts, and chimeric males were bred with B6D2 females for germline transmission. The resulting p18-null mice were maintained on a mixed C57BL/6;129 genetic background for several years. In 2010, p18-/- mice on a mixed C57BL/6;129 genetic background were obtained by Dr. Laurence M. Morel (University of Florida) where they were subsequently backcrossed onto C57BL/6J for approximately five generations - establishing the congenic strain B6.p18-/-. In 2016, B6.p18-/- males with black coat color were sent to The Jackson Laboratory Repository. Upon arrival, sperm was cryopreserved. To establish our live colony, an aliquot of frozen sperm was used to fertilize C57BL/6J oocytes (Stock No. 000664).
Of note, the donating investigator reports that, at least once during backcrossing, a heterozygous female was bred to a C57BL/6J inbred male (thus the Y chromosome of the congenic strain is of C57BL/6J origin).

Allele

Symbol: Cdkn2c^tm1Yxi
Name: targeted mutation 1, Yue Xiong
MGI accession ID: MGI:1933762
Generation method: Targeted
Attributes: Null/Knockout
Synonyms: p18/INK4c^-; p18^-; p18^INK4c-
Marker symbol: Cdkn2c
Marker name: cyclin dependent kinase inhibitor 2C
Marker synonyms: INK4C; p18; p18INK4c; p18-INK4C
Chromosome: 4
Strain of origin: 129/Sv
Molecular note: A neomycin resistance cassette replaced 2kb of sequence containing exon 3, which encodes amino acids 42- 168. No protein was detected in Western blots of immunoprecipitates from lysates derived from heart, kidney, lung, skeletal muscle or spleen of homozygous mutant mice.