Alternative titles; symbols
HGNC Approved Gene Symbol: CSF1
Cytogenetic location: 1p13.3 Genomic coordinates (GRCh38): 1:109,910,506-109,930,992 (from NCBI)
CSF1 is a cytokine required for differentiation of monocyte lineage cells (e.g., tissue macrophages, osteoclasts, and microglia) during development (Kubota et al., 2009).
Kawasaki et al. (1985) isolated cDNA clones encoding human macrophage-specific colony-stimulating factor (CSF1). Although it is a single-copy gene, its expression results in the synthesis of several mRNAs, ranging in size from about 1.5 to 4.5 kb.
Ladner et al. (1987) showed that there are 2 forms of CSF1, with 224 and 522 amino acids, resulting from alternative splicing.
By screening renal cell carcinomas (RCCs) with tumor-infiltrating cytotoxic T-lymphocyte (CTL) clones, followed by cDNA library construction and rescreening, Probst-Kepper et al. (2001) identified an antigen presented by HLA-B*35. The authors determined that this antigen corresponds to fragments encoded by the 5-prime region of CSF1; however, only a peptide encoded by an alternative reading phase could sensitize the CTL. This antigenic alternative CSF1 (alt-CSF1) consists of a 14-amino acid peptide, longer than the usual 8-to-11 mer recognized by most CTLs. Expression of alt-CSF1 could only be detected immunohistochemically in most RCCs and in proximal tubule epithelium and hepatocytes, none of which produce CSF1. Mutational analysis indicated that the 14-mer peptide is anchored to the HLA-B*35 groove at its N and C termini and that the middle part probably bulges out of the groove and is recognized by CTLs. Probst-Kepper et al. (2001) concluded that translation of the major and alt-CSF1 variants is independently controlled.
Pollard et al. (1987) presented evidence that CSF1 has a role in development of the placenta. Uterine CSF1 concentration is regulated by a synergistic action of estradiol and progesterone. CSF1 is produced by uterine glandular epithelial cells. It had been found that FMS, the CSF1 receptor (CSF1R; 164770), is expressed in placenta and choriocarcinoma cell lines.
Using fate mapping analysis, Ginhoux et al. (2010) determined that adult microglia derive from primitive macrophages. Ginhoux et al. (2010) showed that microglia develop in mice that lack CSF1 but are absent in CSF1R-deficient mice. In vivo lineage tracing studies established that adult microglia derive from primitive myeloid progenitors expressing Runx1 that arise before embryonic day 8. Ginhoux et al. (2010) concluded that their results identified microglia as an ontogenically distinct population in the mononuclear phagocyte system and have implications for the use of embryonically derived microglial progenitors for the treatment of various brain disorders.
Mossadegh-Keller et al. (2013) demonstrated that CSF1, a myeloid cytokine released during infection and inflammation, can directly induce the myeloid master regulator PU.1 (165170) and instruct myeloid cell-fate change in mouse hematopoietic stem cells, independently of selective survival or proliferation. Video imaging and single-cell gene expression analysis revealed that stimulation of highly purified hematopoietic stem cells with CSF1 in culture results in activation of the PU.1 promoter and an increased number of PU.1-positive cells with myeloid gene signature and differentiation potential. In vivo, high systemic levels of CSF1 directly stimulated CSF1-receptor-dependent activation of endogenous PU.1 protein in single hematopoietic stem cells and induced a PU.1-dependent myeloid differentiation preference. Mossadegh-Keller et al. (2013) concluded that their data demonstrated that lineage-specific cytokines can act directly on hematopoietic stem cells in vitro and in vivo to instruct a change of cell identity. The authors concluded that this observation fundamentally changed the view of how hematopoietic stem cells respond to environmental challenge and implicated stress-induced cytokines as direct instructors of hematopoietic stem cell fate.
Ladner et al. (1987) showed that the CSF1 gene contains 10 exons and 9 introns spanning 20 kb.
Pettenati et al. (1987) used a CSF1 cDNA probe to map the gene to 5q33.1 by somatic cell hybridization and in situ hybridization in normal chromosomes and in chromosomes with various rearrangements of neoplasia. Morris et al. (1991) demonstrated that the previous assignment to chromosome 5 was in error. They reassigned the gene to 1p21-p13 by in situ hybridization and confirmed the localization by hybridizing a CSF1 cDNA probe to filters containing flow-sorted chromosomes and by identifying CSF1 sequences in DNAs extracted from human/rodent somatic cell hybrids that contained human chromosome 1 but not human chromosome 5. The findings are consistent with studies that have shown tight linkage between the murine CSF1 and amylase genes, as part of a conserved linkage group on mouse chromosome 3 and human 1p. Saltman et al. (1992) likewise localized CSF1 to 1p21-p13 by fluorescence in situ hybridization. (The product of the oncogene FMS (164770) is the CSF1 receptor (CSF1R), which maps to 5q33.2-q33.3. Granulocyte-macrophage colony-stimulating factor (138960) maps to 5q.) Buchberg et al. (1989) localized the murine equivalent gene, Csfm, to chromosome 3 by linkage analysis of interspecific backcrosses.
For discussion of a possible association of variation in the CSF1 gene with susceptibility to Paget disease of bone, see 167250.
Yoshida et al. (1990) established primary fibroblast cell lines from osteopetrotic (op/op) mice and tested the ability of these cell lines to support the proliferation of macrophage progenitors. They showed that the fibroblasts are defective in production of functional macrophage colony-stimulating factor, although the mRNA was present at normal levels. Since the 'op' gene maps to mouse chromosome 3 and the gene called Csfm maps to the same region, they sought a mutation in the Csfm gene of these mice and found a single basepair insertion in the coding region that generated a stop codon 21 basepairs downstream. Mice homozygous for the op mutation suffer from congenital osteopetrosis due to severe deficiency of osteoclasts and macrophages. The unimpaired ability of macrophage progenitors from op/op mice to generate macrophages in vitro when incubated with macrophage growth factors suggested that absence or deficiency of a macrophage growth factor and/or an overabundance of macrophage growth inhibitor was responsible. The op/op mouse is not cured by transplant of normal bone marrow cells, suggesting that the defect is an abnormal hematopoietic microenvironment rather than an intrinsic defect in progenitors of mature macrophages and osteoclasts.
Wiktor-Jedrzejczak et al. (1990) demonstrated that serum, 11 tissues, and different cell- and organ-conditioned media from op/op mice were devoid of biologically active colony-stimulating factor 1, whereas all of these preparations from heterozygous or homozygous normal littermates contained the growth factor. The deficiency was specific for Csf1 in that serum or conditioned media from op/op mice possessed elevated levels of at least 3 other macrophage growth factors. No rearrangement of the Csf1 gene in op/op mice was detected by Southern analysis. However, in contrast to control lung fibroblasts, which contained 4.6- and 2.3-kb Csf1 mRNAs, only the 4.6-kb species was detected in op/op cells.
Blevins and Fedoroff (1995) noted that cell cultures established from the brain of op/op mice required exogenous Csf1 for the development of microglia. In contrast, the brains of adult op/op mice contained normal levels of microglia, suggesting that there exists another activity present in vivo that can substitute for the effect of Csf1 on this cell type.
Studies in op/op mice lacking MCSF have revealed an inhibition of atherosclerosis development in the apolipoprotein E-deficient model and in a diet-induced model (Smith et al., 1995; Qiao et al., 1997). Rajavashisth et al. (1998) used LDL receptor-deficient mice to show that atheroma development depends on MCSF concentration, as not only did homozygous (op/op) mice have dramatically reduced lesions but heterozygous (op/+) mice had lesions less than 1% of controls. These studies supported the conclusion that MCSF participates critically in fatty streak formation and progression to a complex fibrous lesion.
The 'toothless' (tl) mutation in the rat is a naturally occurring, autosomal recessive mutation resulting in a profound deficiency of bone-resorbing osteoclasts and peritoneal macrophages. The failure to resorb bone produces severe, unrelenting osteopetrosis, with a highly sclerotic skeleton, lack of marrow spaces, failure of tooth eruption, and other pathologies. Van Wesenbeeck et al. (2002) identified the genetic lesion in the tl rat as a 10-bp insertion near the beginning of the open reading frame of the Csf1 gene, yielding a truncated, nonfunctional protein and an early stop codon. Thus, the tl rat is Csf1-null. All mutants were homozygous for the mutation and all carriers were heterozygous. In the op mouse, which shows milder osteoclastopenia and osteopetrosis, with spontaneous recovery over the first few months of life, the causative mutation is a single base insertion that disrupts the reading frame.
Niida et al. (2005) stated that Csf1-null mice are osteopetrotic and that those null for the Flt1 gene (165070) show mild osteoclast reduction without bone marrow suppression. They created double-knockout mice that exhibited severe osteoclast deficiency and did not have sufficient osteoclasts to form the bone marrow cavity. The cavity of double-knockout mice was gradually replaced with fibrous tissue, resulting in severe marrow hypoplasia and extramedullary hematopoiesis. The number of osteoblasts was also decreased. Niida et al. (2005) concluded that FLT1 and CSF1 receptors play predominant roles in osteoclastogenesis and the maintenance of bone marrow function.
Using op/op mice and immunohistochemistry, Kubota et al. (2009) found that Mcsf contributed to both vascular and lymphatic development and was required for retinal pathologic neovascularization, but not for maintenance of stable adult vasculature or lymphatics. An osteosarcoma mouse model showed that Mcsf inhibition selectively suppressed tumor angiogenesis and lymphangiogenesis. Interruption of Mcsf inhibition, unlike blockade of Vegf (192240), did not promote rapid tumor growth. Kubota et al. (2009) proposed that therapy targeting MCSF could be useful in treating ocular neovascular disease and cancer.
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