Colony-stimulating factor 1 (CSF-1) regulates the survival, proliferation, and differentiation of mononuclear phagocytes. It is expressed as a secreted glycoprotein or proteoglycan found in the circulation or as a biologically active cell-surface glycoprotein. There are two forms of CSF1, with 224 and 522 amino acids, resulting from alternative splicing (Kawasaki et al, 1985).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. The CSF1 receptor (product of the oncogene c-fms), is expressed in placenta and choriocarcinoma cell lines. CSF-1 is neurotrophic in embryonic neuronal cultures and its absence in csfmop/csfmop mice results in severe electro-physiological abnormalities in the cortex. This suggests that CSF-1 is a neurotrophic factor acting through the microglia. The pleiotropic roles for CSF-1 in reproduction and in the brain suggest that CSF-1 exerts many of its action through the trophic activities of cells of the mononuclear phagocytic lineage.
NCBI Summary:
The protein encoded by this gene is a cytokine that controls the production, differentiation, and function of macrophages. The active form of the protein is found extracellularly as a disulfide-linked homodimer, and is thought to be produced by proteolytic cleavage of membrane-bound precursors. The encoded protein may be involved in development of the placenta. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Sep 2011]
General function
Ligand, Cytokine
Comment
Keshava et al., (1999) show, that CSF-1 is capable of inducing its own receptor (c-fms). Furthermore, they show the interdependent role of CSF-1 and c-fms genes in transformation of normal ovarian granulosa cells to a tumorigenic phenotype. They suggest the possibility of a similar role for these genes in progression of ovarian cancer. Results shown by Suzuki et al. (1998), suggest that M-CSF is highly sensitive and specific for malignant germ cell tumors of the ovary, especially for dysgerminoma.
Cellular localization
Comment
Ovarian function
Ovulation, Steroid metabolism, Oogenesis, Early embryo development
Comment
Role of macrophage colony-stimulating factor (M-CSF) in human granulosa cells. Xu S et al. (2016) Macrophage colony-stimulating factor (M-CSF) has been proved to have a positive role in the follicular development. We investigated its effect on human granulosa cells and found that M-CSF could stimulate the production of E2. The production of FSH receptors was enhanced by M-CSF in vitro in a dose-dependent manner with or without the addition of tamoxifen (p <0.05). Correspondingly, FSH was also able to coordinate the expression of M-CSF and its receptor (p <0.05). That maybe important to maintain the level of Nppc and the meiotic arrest of the oocyte. The protein p-JAK2 and p-STAT3 in JAK/STAT-signaling pathway elevated after the influence of M-CSF (p < 0.05). These results suggest that M-CSF has a role in regulating the response of granulosa cells to gonadotropins. Its function is associated with JAK/STAT-signaling pathway.//////////////////
Clinical use of colony-stimulating factor-1 in ovulation induction for poor responders. Takasaki A et al. OBJECTIVE: To evaluate the benefit of colony-stimulating factor-1 (CSF-1) adjuvant therapy to poor responders during a controlled ovarian hyperstimulation (COH) cycle. DESIGN: Prospective clinical study. SETTING: University hospital, general hospital, and private IVF clinic in Japan. PATIENT(S): Thirty normogonadotropic patients who did not respond to conventional COH protocols. INTERVENTION(S): Eight million units of recombinant human CSF-1 were administered IV every other day during ovarian stimulation using FSH or hMG to 30 normogonadotropic poor responders. Serum CSF-1 concentrations were assayed on day 3. Additional studies were performed in a private IVF clinic on 27 poor responders with low serum CSF-1 levels. MAIN OUTCOME MEASURE(S): Pregnancy rates (PR). In addition, number of mature follicles, cycle cancellations, amount of required gonadotropins were documented. RESULT(S): Significantly more mature follicles, fewer cycle cancellations, and lower amounts of required gonadotropins were seen in the group treated with CSF-1. Five (16.7%) pregnancies were achieved. The CSF-1-effective patients displayed significantly lower serum CSF-1 concentrations. In a private IVF clinic, CSF-1 treatment increased the number of mature oocytes, fertilized eggs, and transferred embryos. Cycle cancellations decreased from 18.5%-3.7%; 11 pregnancies (40.7%) resulted from treatment. CONCLUSION(S): Concomitant administration of CSF-1 and hMG improved follicle developments, especially in patients with low serum CSF-1 levels in the early follicular phase.
CSF-1 concentrations in follicular fluid showed significantly higher values during the ovulatory phase compared to mid-follicular phase (Shinetugs et al, 1999).
Results of Nishimura et al. (1998) suggest, that gonadotropins lead to an increase in ovarian MCSF1 production. Thus, macrophage colony-stimulating factor may play an important role in the process of follicular maturation and ovulation as an intraovarian regulator.
Pollard, 1997, reviewed the phenotype of CSF-1-deficient mice. In both sexes, CSF-1 appears to regulate gonadal steroidogenesis, probably through its action on macrophages that are abundant throughout the ovary and testis. In the female, CSF-1 affects ovulation in vivo and in vitro, and influences the preimplantation embryo, increasing both its rate of development and the number of trophectodermal cells in the blastocyst.
Expression regulated by
mir423-5p
Comment
MiR-423-5p may regulate ovarian response to ovulation induction via CSF1. Xie S et al. (2020) We have previously shown that hsa-miR-423-5p expression in ovarian granulosa cells is decreased in high ovarian response populations. The objective of the present study was to find the target gene and mechanism for miR-423-5p involved in ovarian response regulation. (a) TargetScan was used to predict the target gene of hsa-miR-423-5p. (b) A model for hsa-miR-423-5p overexpression or inhibition was constructed by transfecting KGN cells with lentivirus. CSF1 mRNA and protein expression and luciferase activity were measured. (c) The cell cycles of control and lentivirus treated KGN cells were analyzed. Western blot was used to measure the expression of CDKN1A in KGN cells. (d) The concentration of E2 in KGN cell culture medium were measured. (a) TargetScan revealed that the 3' un-translated region of CSF1 matched 11 bases at the 5' end of miR-423-5p, making it a likely target gene. (b) Overexpression or inhibition of miR-423-5p were associated with respective decreases or increases in CSF1 expression (both mRNA and protein) (p < 0.05) and luciferase activity (p < 0.05). (c) When miR-423-5p expression increased, the number of G0/G1 phase cells and the expression of CDKN1A protein increased while estradiol concentrations in the cell culture solution decreased (p < 0.05). However, when miR-423-5p expression decreased, the number of S phase cells increased and E2 concentrations increased while the expression of CDKN1A protein decreased (p < 0.05). Colony stimulating factor 1 is a target gene of miR-423-5p and that it may regulate ovarian response to ovulation induction by affecting granulosa cells proliferation and estrogen secretion.//////////////////
Ovarian localization
Granulosa
Comment
Ryan GR, et al reported the rescue of the colony-stimulating factor 1 (CSF-1)-nullizygous mouse (Csf1(op/)Csf1(op))
phenotype with a CSF-1 transgene and identification of sites of local CSF-1 synthesis. To investigate tissue CSF-1 regulation,
CSF-1-null Csf1(op)/Csf1(op) mice expressing transgenes encoding the full-length membrane-spanning CSF-1 precursor driven
by 3.13 kilobases of the mouse CSF-1 promoter and first intron were characterized. Transgene expression corrected the
gross osteopetrotic, neurologic, weight, tooth, and reproductive defects of Csf1(op)/Csf1(op) mice. Detailed analysis of one
transgenic line revealed that circulating CSF-1, tissue macrophage numbers, hematopoietic tissue cellularity, and
hematopoietic parameters were normalized. Also, lacZ driven by the same promoter/first intron revealed beta -galactosidase
expression in hematopoietic, reproductive, and other tissue locations proximal to CSF-1 cellular targets, consistent with local
regulation by CSF-I at these sites. These studies indicate that the 3.13-kilobase promoter/ first intron confers essentially
normal CSF-1 expression. They also pinpoint new cellular sites of CSF-1 expression, including ovarian granulosa cells,
mammary ductal epithelium, testicular Leydig cells, serous acinar cells of salivary gland, Paneth cells of the small intestine,
as well as local sites in several other tissues.
Follicle stages
Comment
Expression of mRNA and protein of macrophage colony-stimulating factor and its receptor in human follicular luteinized granulosa cells Salmassi A, et al .
OBJECTIVE: To evaluate the concentration of macrophage colony-stimulating factor (M-CSF) in serum and follicular fluid (FF) at the time of oocyte retrieval and to detect expression of M-CSF and its receptor by luteinized granulosa cells (GCs). DESIGN: Collection of serum and FF at the time of oocyte retrieval. SETTING: A university IVF- intracytoplasmic sperm injection (ICSI) program. PATIENT(S): Serum and FF were obtained from 85 women undergoing oocyte retrieval. INTERVENTION(S): Serum and FF were obtained from 85 women. The GCs were pooled from 15 (3 x 5) patients (3-14 oocytes each). MAIN OUTCOME MEASURE(S): The M-CSF concentration was determined by ELISA, the expression of M-CSF and its receptor by the immunocytochemical technique and reverse transcription polymerase chain reaction analysis. In addition, M-CSF expression was investigated by cell culture time course studies. RESULTS: The median M-CSF concentration in FF (2,409.2 pg/mL) was significantly higher than that in serum (242.5 pg/mL). The M-CSF and its receptor were expressed by GCs. CONCLUSION(S): The significantly higher level of M-CSF in FF than in serum and the expression of M-CSF and its receptor in FF by GCs suggest an important role for this growth factor in ovarian function.
Phenotypes
Mutations
1 mutations
Species: mouse
Mutation name: csfmopscfmop/csfmop, osteopetrotic mice
type: null mutation fertility: subfertile Comment: CSF-1-deficient, osteopetrotic (csfmop/csfmop) mice suffer from low pregnancy rates and smaller litter sizes compared to wild-type mice. Females have extended estrous cycles compared to wild-type females, and s.c. administration of CSF-1 from birth restores estrous cyclicity (Araki et al, 1996). These mice fail to display the characteristic proestrous surge in circulating estradiol-17beta. However, concentrations of this hormone
are normal during the remainder of the cycle. Furthermore, csfmop/csfmop females have significantly lower ovulation rates than wild-type mice, but the implantation rates of fertilized oocytes are normal. Thus, the major effect of CSF-1 on female reproductive function is on the frequency and rate of ovulation, indicating a major role for this growth factor in regulating follicular development and ovulation. (Cohen et al, 1997).