B6.129S6-Pdcd4^tm1Yhcn/J

Stock number: 018164
Research areas: Immunology, Inflammation and Autoimmunity Research, Research Tools

Description

This knockout mutant of the Pdcd4 (programmed cell death 4) gene exhibits reduced cytokine secretion, lower susceptibility to LPS challenge and EAE, resistance to STZ- induced diabetes, and develops spontaneous lymphoma.

Detailed description

The programmed cell death 4 protein is a proinflammatory agent and tumor suppressor that also inhibits translation initiation and cap-dependent translation. MicroRNA-21 (miR-21) downregulates Pdcd4 expression post-translationally. Mice homozygous for this knockout mutation of Pdcd4 are viable and fertile, however 86% of homozygotes die due to lymphoma by 106 weeks of age (mean life expectancy of homozygotes is reduced to 101 weeks). At approximately 20 months of age, many homozygotes develop spontaneous lymphoma (primarily diffuse B cell), often with metastasis to liver and kidney. Approximately half of homozygotes at 20 weeks of age exhibit kidney, ovary, or prostate cysts. No Pdcd4 mRNA or protein is detected by Northern or Western blot analysis of thymus. Homozygotes are resistant to STZ (streptozotocin) induced diabetes (5% compared to 59% in controls), and exhibit reduced severity and mortality of EAE (experimental autoimmune encephalomyelitis). IL-4, IL-10, and IFNG cytokine secretion is elevated in homozygous animals. Homozygotes display reduced susceptibility to and lower circulating IL-6 levels after lipopolysaccharide (LPS) challenge, and lower resulting mortality compared to wildtype controls. During backcrossing, the Y chromosome may not have been fixed to the C57BL/6J genetic background.

Development

A targeting vector containing a neomycin resistance gene was used to disrupt exons 3 and 4. The construct was electroporated into 129S6/SvEvTac derived TL1 embryonic stem (ES) cells. Correctly targeted ES cells were injected into C57BL/6J blastocysts. The resulting male chimeric animals were crossed to C57BL/6J female mice, and then backcrossed to C57BL/6 for at least 5 generations. Upon arrival at The Jackson Laboratory, the mice were crossed to C57BL/6J (Stock No. 000664) at least once to establish the colony.

Allele

Symbol: Pdcd4^tm1Yhcn
Name: targeted mutation 1, Youhai H Chen
MGI accession ID: MGI:3707444
Generation method: Targeted
Attributes: Null/Knockout
Marker symbol: Pdcd4
Marker name: programmed cell death 4
Chromosome: 19
Strain of origin: 129S6/SvEvTac
Molecular note: A targeting vector was designed to replace exons 3 and 4 with a neomycin resistance cassette. Absence of protein was confirmed in mutant lymphoid organs.