Abstract
Macrophage colony-stimulating factor (CSF1 or M-CSF) and interleukin 34 (IL34) are secreted cytokines that control macrophage survival and differentiation. Both act through the CSF1 receptor (CSF1R), a type III transmembrane receptor tyrosine kinase. The functions of CSF1R and both ligands are conserved in birds. We have analyzed protein-coding sequence divergence among avian species. The intracellular tyrosine kinase domain of CSF1R was highly conserved in bird species as in mammals but the extracellular domain of avian CSF1R was more divergent in birds with multiple positively selected amino acids. Based upon crystal structures of the mammalian CSF1/IL34 receptor-ligand interfaces and structure-based alignments, we identified amino acids involved in avian receptor-ligand interactions. The contact amino acids in both CSF1 and CSF1R diverged among avian species. Ligand-binding domain swaps between chicken and zebra finch CSF1 confirmed the function of variants that confer species specificity on the interaction of CSF1 with CSF1R. Based upon genomic sequence analysis, we identified prevalent amino acid changes in the extracellular domain of CSF1R even within the chicken species that distinguished commercial broilers and layers and tropically adapted breeds. The rapid evolution in the extracellular domain of avian CSF1R suggests that at least in birds this ligand-receptor interaction is subjected to pathogen selection. We discuss this finding in the context of expression of CSF1R in antigen-sampling and antigen-presenting cells.
Highlights
Macrophage colony-stimulating factor (CSF1 or M-CSF) is a hematopoietic growth factor that regulates the survival, proliferation, and differentiation of mononuclear phagocytes.[1,2,3] CSF1 signals through a type III tyrosine kinase (TK) CSF1 receptor (CSF1R, known as MCSFR, or c-Fms and recognized by anti-CD115 antibodies), which is expressed on the surface of macrophages, monocytes, and their progenitors
The sequences annotated as CSF1 or interleukin 34 (IL34) in National Centre for Biotechnology Information (NCBI) as a predicted protein were truncated at the N terminus relative to full-length chicken and zebra finch orthologs
How can the specificity of interaction between a single receptor and two ligands be maintained through evolution in the face of pathogen selection? We might have anticipated conservation of key amino acids involved in ligand recognition, but where the topology of interaction is conserved, the precise contacts have changed
Summary
Macrophage colony-stimulating factor (CSF1 or M-CSF) is a hematopoietic growth factor that regulates the survival, proliferation, and differentiation of mononuclear phagocytes.[1,2,3] CSF1 signals through a type III tyrosine kinase (TK) CSF1 receptor (CSF1R, known as MCSFR, or c-Fms and recognized by anti-CD115 antibodies), which is expressed on the surface of macrophages, monocytes, and their progenitors. Since macrophages control many aspects of tissue regeneration, inflammation, and pathology, CSF1R signaling has been considered a target for the development of therapeutic agonists and antagonists (reviewed in Ref. 2). Loss-of-function (LOF) mutations in the CSF1 and CSF1R loci in mice and rats are associated with depletion of blood monocytes and most tissue macrophage populations.
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