Genetic disruption of the murine complement C3 promoter region generates deficient mice with extrahepatic expression of C3 mRNA

Genetic deficiencies of the complement protein C3 occur naturally in humans and animal models and have been induced in mice by targeted deletion of th e C3 gene. The study of these deficiencies has provided evidence for C3 fun ctions in immune responses. C3 deficient mice were generated by replacing t he 5'-flanking region of the C3 gene with the neomycin-resistance (neo) gen e. Serum from these mice had no detectable C3 protein or complement activit y. Challenge with Streptococcus pneumoniae revealed approximately 2000-fold increase in bacteremia as compared to littermate controls. C3 mRNA was abs ent in the liver, but it was detected in the lung, kidney, fat tissue, hear t and spleen. Metabolic labeling of the lung tissue and peritoneal macropha ges showed synthesis of pro-C3, but no post-synthetic intracellular process ing of the protein and no secretion of mature C3, cDNA analysis at the cap site indicated that extrahepatic transcription of the targeted gene was ini tiated in the neo cassette, close to the C3/neo junction and predicted a pr imary translation product lacking the leader peptide. The data indicate tha t these mice provide a good animal model for the study of complete C3 defic iencies and a potential probe for tissue-specific C3 gene regulatory elemen ts. (C) 1999 Elsevier Science B.V. All rights reserved.