Pleiotropic impacts of macrophage and microglial deficiency on development in rats with targeted mutation of the Csf1r locus

Clare Pridans, Anna Raper, Gemma M. Davis, Joana Alves, Kristin A. Sauter, Lucas Lefevre, Tim Regan, Stephen Meek, Linda Sutherland, Alison J. Thomson, Sara Clohisey, Stephen J. Bush, Rocío Rojo, Zofia M. Lisowski, Robert Wallace, Kathleen Grabert, Kyle R Upton, Yi Ting Tsai, Deborah Brown, Lee B. SmithKim M. Summers, Neil A. Mabbott, Pedro Piccardo, Michael T. Cheeseman, Tom Burdon, David A. Hume

Research output: Contribution to journalArticlepeer-review

Abstract

We have produced Csf1r-deficient rats by homologous recombination in embryonic stem cells. Consistent with the role of Csf1r in macrophage differentiation, there was a loss of peripheral blood monocytes, microglia in the brain, epidermal Langerhans cells, splenic marginal zone macrophages, bone-associated macrophages and osteoclasts, and peritoneal macrophages. Macrophages of splenic red pulp, liver, lung, and gut were less affected. The pleiotropic impacts of the loss of macrophages on development of multiple organ systems in rats were distinct from those reported in mice. Csf1r2/2 rats survived well into adulthood with postnatal growth retardation, distinct skeletal and bone marrow abnormalities, infertility, and loss of visceral adipose tissue. Gene expression analysis in spleen revealed selective loss of transcripts associated with the marginal zone and, in brain regions, the loss of known and candidate novel microglia-associated transcripts. Despite the complete absence of microglia, there was little overt phenotype in brain, aside from reduced myelination and increased expression of dopamine receptor-associated transcripts in striatum. The results highlight the redundant and nonredundant functions of CSF1R signaling and of macrophages in development,
organogenesis, and homeostasis.
Original languageEnglish
Pages (from-to)2683-2699
JournalJournal of Immunology
Volume201
Issue number9
Early online date24 Sep 2018
DOIs
Publication statusPublished - 1 Nov 2018

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