These CCAAT/enhancer binding protein (C/EBP), beta knock-out mutant mice may be useful in studying metabolism, obesity, mammary gland development, or lymphoproliferative disorders.
Colleen Croniger, Case Western Reserve University
Significant numbers of mice homozygous for this C/EBP-beta mutation on this mixed genetic background die perinatally due to hypoglycemia and a failure to mobilize glycogen. Homozygous males that survive to adulthood are fertile, but females are sterile, and display altered mammary duct formation. Macrophages isolated from homozygous mutant mice have impaired bactericidal activity. Surviving homozygotes exhibit fasting hypoglycemia, with reduced plasma insulin, plasma lipids, and free fatty acids (FFAs), and impaired hepatic glucose production. Further, they have a blunted response to glucagon and adrenaline primarily due to altered levels of hepatic cAMP production and reduced protein kinase A activity. Homozygous mice are resistant to obesity and have increased carbon dioxide production from increased metabolism in the brown adipose tissue and muscle. On a high-fat diet, homozygotes are protected from obesity and fatty liver due to reduced hepatic expression of lipogenic genes. Homozygotes may also exhibit a hematopoietic/lymphoproliferative disorder resembling Castleman's disease in humans. These C/EBP-beta mutant mice may be useful in studying metabolism, obesity, mammary gland development, or lymphoproliferative disorders.
A targeting vector was used to replace the carboxy-terminal 72 amino acids of the protein which codes for the leucine zipper and part of the basic domain, with an MCI-Neo poly(A)+ cassette. This construct was electroporated into 129S/SvEv-Gpi1c-derived CCE embryonic stem (ES) cells, and correctly targeted ES cells were microinjected into C57BL/6 blastocysts. Male chimeras were mated to outbred MF1 females to obtain heterozygous offspring. Heterozygous mice were bred together to generate homozygous mice on this mixed 129S and MF1 genetic background.
|Allele Name||targeted mutation 1, Valeria Poli|
|Allele Type||Targeted (Null/Knockout)|
|Allele Synonym(s)||C/EBPb-; C/EBPbeta-; Cebpb-|
|Gene Symbol and Name||Cebpb, CCAAT/enhancer binding protein (C/EBP), beta|
|Gene Synonym(s)||C/EBP BETA; C/EBP-beta; C/EBPbeta; CRP2; IL-6DBP; IL6DBP; Il6dbp; LAP; LIP; NF-IL6; NF-M; Nfil6; Nfil6; TCF5; nuclear protein Il6|
|Strain of Origin||129S/SvEv-Gpi1 |
|General Note||Phenotypic Similarity to Human Syndrome: Multi-centric Castleman's Disease (J:25215) |
Mice homozygous for this targeted mutation exhibit a pathology that is almost identical to multicentric Castleman's disease in human patients, characterized by splenomegaly, peripheral lymphoadenopathy, enhanced hematopoiesis, and deregulated IL-6 production (J:25215).
|Molecular Note||An MC1-neocassette replaced the carboxy-terminal part of the gene, which encodes the leucine zipper and part of the basic domain. Generation of a null allele was confirmed by Western blots of hepatic tissue nuclear extracts.|
|Mutations Made By|| |
Valeria Poli, University of Dundee
When maintaining a live colony, heterozygous mice are bred together or to wildtype siblings. The donating investigator reports increased penetrance of perinatal lethality when backcrossed to C57BL/6 genetic background.
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