Journal
JOURNAL OF EXPERIMENTAL MEDICINE
Volume 210, Issue 12, Pages 2539-2552Publisher
ROCKEFELLER UNIV PRESS
DOI: 10.1084/jem.20131274
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Funding
- Collegio Ghislieri, Pavia, Italy
- Swiss National Science Foundation (SNF)
- Canadian Institutes of Health Research (CIHR) [64216]
- Genome Canada
- Juvenile Diabetes Research Foundation [17-2011-520]
- European Union (LUPAS, PRIORITY)
- SNF
- Clinical Research Focus Program of the University of Zurich
- Foundation Alliance BioSecure
- Novartis Research Foundation
- Advanced Grant of the European Research Council
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Prnp(-/-) mice lack the prion protein PrPC and are resistant to prion infections, but variable phenotypes have been reported in Prnp(-/-) mice and the physiological function of PrPC remains poorly understood. Here we examined a cell-autonomous phenotype, inhibition of macrophage phagocytosis of apoptotic cells, previously reported in Prnp(-/-) mice. Using formal genetic, genomic, and immunological analyses, we found that the regulation of phagocytosis previously ascribed to PrPC is instead controlled by a linked locus encoding the signal regulatory protein. (Sirpa). These findings indicate that control of phagocytosis was previously misattributed to the prion protein and illustrate the requirement for stringent approaches to eliminate confounding effects of flanking genes in studies modeling human disease in gene-targeted mice. The plethora of seemingly unrelated functions attributed to PrPC suggests that additional phenotypes reported in Prnp(-/-) mice may actually relate to Sirpa or other genetic confounders.
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