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A novel mouse model expressing human forms for complement receptors CR1 and CR2

Jackson, Harriet M., Foley, Kate E., O'Rourke, Rita, Stearns, Timothy M., Fathalla, Dina, Morgan, B. Paul and Howell, Gareth R. 2020. A novel mouse model expressing human forms for complement receptors CR1 and CR2. BMC Genetics 21 (1) , 101. 10.1186/s12863-020-00893-9

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Background The complement cascade is increasingly implicated in development of a variety of diseases with strong immune contributions such as Alzheimer’s disease and Systemic Lupus Erythematosus. Mouse models have been used to determine function of central components of the complement cascade such as C1q and C3. However, species differences in their gene structures mean that mice do not adequately replicate human complement regulators, including CR1 and CR2. Genetic variation in CR1 and CR2 have been implicated in modifying disease states but the mechanisms are not known. Results To decipher the roles of human CR1 and CR2 in health and disease, we engineered C57BL/6J (B6) mice to replace endogenous murine Cr2 with human complement receptors, CR1 and CR2 (B6.CR2CR1). CR1 has an array of allotypes in human populations and using traditional recombination methods (Flp-frt and Cre-loxP) two of the most common alleles (referred to here as CR1long and CR1short) can be replicated within this mouse model, along with a CR1 knockout allele (CR1KO). Transcriptional profiling of spleens and brains identified genes and pathways differentially expressed between mice homozygous for either CR1long, CR1short or CR1KO. Gene set enrichment analysis predicts hematopoietic cell number and cell infiltration are modulated by CR1long, but not CR1short or CR1KO. Conclusion The B6.CR2CR1 mouse model provides a novel tool for determining the relationship between human-relevant CR1 alleles and disease.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
Publisher: BioMed Central
ISSN: 1471-2156
Date of First Compliant Deposit: 30 September 2020
Date of Acceptance: 21 July 2020
Last Modified: 01 Oct 2020 09:30

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