Regulation of Embryonic and Postnatal Development by the CSF-1 Receptor

Abstract

Macrophages are found in all tissues and regulate tissue morphogenesis during development through trophic and scavenger functions. The colony stimulating factor-1 (CSF-1) receptor (CSF-1R) is the major regulator of tissue macrophage development and maintenance. In combination with receptor activator of nuclear factor κB (RANK), the CSF-1R also regulates the differentiation of the bone-resorbing osteoclast and controls bone remodeling during embryonic and early postnatal development. CSF-1R-regulated macrophages play trophic and remodeling roles in development. Outside the mononuclear phagocytic system, the CSF-1R directly regulates neuronal survival and differentiation, the development of intestinal Paneth cells and of preimplantation embryos, as well as trophoblast innate immune function. Consistent with the pleiotropic roles of the receptor during development, CSF-1R deficiency in most mouse strains causes embryonic or perinatal death and the surviving mice exhibit multiple developmental and functional deficits. The CSF-1R is activated by two dimeric glycoprotein ligands, CSF-1, and interleukin-34 (IL-34). Homozygous Csf1-null mutations phenocopy most of the deficits of Csf1r-null mice. In contrast, Il34-null mice have no gross phenotype, except for decreased numbers of Langerhans cells and microglia, indicating that CSF-1 plays the major developmental role. Homozygous inactivating mutations of the Csf1r or its ligands have not been reported in man. However, heterozygous inactivating mutations in the Csf1r lead to a dominantly inherited adult-onset progressive dementia, highlighting the importance of CSF-1R signaling in the brain.

Microglia are necessary for toxin-mediated demyelination and activation of microglia is sufficient to induce demyelination

“…This also agrees with data indicating that the CSF1 receptor, i.e. CSF1r, is expressed by microglia but not by other cells in the adult CNS (Chitu & Stanley, 2017;Y. Zhang et al, 2014).…”

The roles of CSFs on the functional polarization of tumor‐associated macrophages

“…These mice have an even more severe phenotype than csf1 op / op mice and exhibit poorer viability, supporting the existence of another CD115 ligand which has been subsequently identified as IL‐34 . Supporting an important role in tissue development, csf1r −/− mice, as observed in csf1 op/op mice, have perturbations in tissues development (bone, pancreas, mammary gland) . Finally, depletion studies demonstrate a central role of the M‐CSF‐CD115 axis in the maintenance of macrophage homeostasis in tissues .…”

“…Mice with a null mutation of the csf1r gene ( csf1r −/− mice) also exhibit a severe depletion in macrophage populations, confirming that CSF‐1R/CD115 is the only receptor for M‐CSF. These mice have an even more severe phenotype than csf1 op / op mice and exhibit poorer viability, supporting the existence of another CD115 ligand which has been subsequently identified as IL‐34 . Supporting an important role in tissue development, csf1r −/− mice, as observed in csf1 op/op mice, have perturbations in tissues development (bone, pancreas, mammary gland) .…”

Transcriptional network analysis of transcriptomic diversity in resident tissue macrophages and dendritic cells in the mouse mononuclear phagocyte system

“…Igf1 is CSF1-inducible and of particular interest because of the profound impact of Csf1r mutations in multiple species on postnatal growth and development [7]. Unlike hepatocytes and mesenchymal cells, tissue macrophages did not express transcripts encoding the growth hormone receptor (Ghr), Igf1r, or the Igf1 binding protein genes (Igfals, Igfbp1, 2,3,5,6). The exception is Igfbp4 which was highly-expressed in most macrophage populations and did form part of the Lyve1/Mrc1-associated Cluster 22.…”

“…Within each tissue, resident macrophages occupy territories with a regular distribution, commonly associated with epithelial and endothelial surfaces (reviewed in [5]). The proliferation, differentiation and survival of most resident macrophage populations depends upon signals from the macrophage-colony-stimulating factor receptor (CSF1R) initiated by one of two ligands, CSF1 or IL34 [6,7]. Based upon detection of macrophage-restricted mRNA, including Csf1r, the relative abundance of resident macrophages in most organs in mice was shown to reach a maximum in the first week of postnatal life and remains stable thereafter during postnatal growth [8].…”