Functional evolution of the colony-stimulating factor 1 receptor (CSF1R) and its ligands in birds

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 antigensampling and antigen-presenting cells.

Measurement of serum Interleukin 34 (IL‐34) and correlation with severity and pruritus scores in client‐owned dogs with atopic dermatitis

“…5,15 To date, the study of IL-34 and its receptor complex in other species has been limited to zebrafish, avian species, feline and porcine studies. [16][17][18][19] Following its discovery in 2008, early evidence suggested that IL-34 was indistinguishable in its biological activity from colony stimulating factor 1 (CSF1). Before this time, CSF1 was the single well-characterized ligand for CSF1R.…”

Analysis of the Progeny of Sibling Matings Reveals Regulatory Variation Impacting the Transcriptome of Immune Cells in Commercial Chickens

“…There is a strong signature of selection over the CSF1R locus in commercial broilers (Stainton et al, 2017). Analysis of the genomic sequence data for commercial birds (Gheyas et al, 2015) revealed high prevalence non-synonymous protein-coding variants in CSF1R that are unique to either broilers or layers (Hume et al, 2019). In support of the possibility that this variation is functionally significant, mutations in either Csf1r or Csf1 in both mice and rats produce severe post-natal growth retardation (Dai et al, 2002; Pridans et al, 2018).…”

M-CSFR/CSF1R signaling regulates myeloid fates in zebrafish via distinct action of its receptors and ligands

“…[3][4][5][6] However, despite the fact that both of these cytokines bind to the same receptor and can equally support cell growth and survival, they achieve this by triggering different chemokine responses. 4,7 The CSF1R signaling pathway is in general critical for the proliferation, differentiation, survival, and activation of mononuclear phagocytic cells (MPCs) such as monocytes, macrophages, osteoclasts, or microglia in mammals, [8][9][10] birds, 11,12 and fish. 13 Deregulation of the CSF1R pathway was connected to disease phenotypes 14 such as osteopetrosis, 9,10,15,16 brain disease, [17][18][19][20] or cancer.…”