Effect of granulocyte-macrophage colony-stimulating factor deficiency on ovarian follicular cell function

Gilchrist, R. B.; Rowe, DB; Ritter, Lesley J.; Robertson, Sarah A.; Norman, Rob; Armstrong, D.T.

doi:10.1530/jrf.0.1200283

Cited by 12 publications

(7 citation statements)

References 22 publications

(42 reference statements)

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“…GM-CSF is expressed in the ovary and experiments in GMϪ/Ϫ mice implicate this factor in folliculogenesis [53] and in the development and steroidogenic function of the corpus luteum during early pregnancy [54]. Our finding of reduced cell number in blastocysts grown in vitro from GMϪ/Ϫ two-cell embryos, irrespective of GM-CSF supplementation of the media, is consistent with the view that oocytes derived from a GM-CSF-deficient follicular environment have diminished developmental competence.…”

Section: Discussionsupporting

confidence: 89%

Granulocyte-Macrophage Colony-Stimulating Factor Promotes Glucose Transport and Blastomere Viability in Murine Preimplantation Embryos1

Robertson

Sjöblom

Jasper

et al. 2001

Biology of Reproduction

169

128

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Granulocyte-macrophage colony-stimulating factor (GM-CSF) secretion from epithelial cells lining the female reproductive tract is induced during early pregnancy by ovarian steroid hormones and constituents of seminal plasma. In this study we have investigated the influence of GM-CSF on development of preimplantation mouse embryos. Blastocyst-stage embryos were found to specifically bind (125)I-GM-CSF and analysis of GM-CSF mRNA receptor expression by reverse transcriptase-polymerase chain reaction indicated expression of the low-affinity alpha subunit of the GM-CSF receptor, but not the affinity-converting beta subunit (beta(c)), or GM-CSF ligand. GM-CSF receptor mRNA was present in the fertilized oocyte and all subsequent stages of development, and in blastocysts it was expressed in both inner cell mass and trophectoderm cells. In vitro culture of eight-cell embryos in recombinant GM-CSF accelerated development of blastocysts to hatching and implantation stages, with a maximum response at a concentration of 2 ng/ml (77 pM). Blastocysts recovered from GM-CSF-null mutant (GM-/-) mice on Day 4 of natural pregnancy or after superovulation showed retarded development, with the total cell number reduced by 14% and 18%, respectively, compared with GM+/+ embryos. Blastocysts generated in vitro from two-cell GM-/- and GM+/+ embryos were larger when recombinant GM-CSF was added to the culture medium (20% and 24% increases in total cell numbers in GM+/+ and GM-/- blastocysts, respectively). Incubation of blastocysts with recombinant GM-CSF elicited a 50% increase in the uptake of the nonmetabolizable glucose analogue, 3-O-methyl glucose. In conclusion, these data indicate that GM-CSF signaling through the low-affinity GM-CSF receptor in blastocysts is associated with increased glucose uptake and enhanced proliferation and/or viability of blastomeres. Together, the findings implicate a physiological role for maternal tract-derived GM-CSF in targeting the preimplantation embryo, and suggest that defective blastocyst development contributes to compromised pregnancy outcome in GM-CSF-null mutant mice.

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Section: Discussionsupporting

confidence: 89%

Granulocyte-Macrophage Colony-Stimulating Factor Promotes Glucose Transport and Blastomere Viability in Murine Preimplantation Embryos1

Robertson

Sjöblom

Jasper

et al. 2001

Biology of Reproduction

169

128

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“…This means that immature, germinal vesicle-stage oocytes first express the factor around the time of antrum formation and continue expression throughout antral development and during oocyte meiotic maturation. Although COC from mice deficient in granulocyte-macrophage colony stimulating factor have nearly twice the number of cumulus cells per COC compared to wild-type mice, the growth-promoting activity of these oocytes is not higher [34]. A soluble, heat-stable factor(s) secreted by the oocyte also regulates granulosa cell steroidogenesis in a dose-dependent manner.…”

Section: Discussionmentioning

confidence: 99%

Oocyte-Secreted Factor(s) Determine Functional Differences Between Bovine Mural Granulosa Cells and Cumulus Cells1

Li¹,

Norman²,

Armstrong³

et al. 2000

Biology of Reproduction

181

136

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Cumulus cells and mural granulosa cells (MGC) are phenotypically different and there is now evidence suggesting that the oocyte plays an active role in determining the fate of follicular somatic cells. This study investigates the role of oocyte-secreted factor(s) in the regulation of the growth and differentiation of cumulus and MGC. Bovine cumulus-oocyte complexes (COC) and MGC were cultured with various hormones for 18 h followed by a further 6-h pulse of [(3)H]thymidine as an indicator of follicular cell DNA synthesis. The COC incorporated 11 to 14 times more [(3)H]thymidine than MGC in either the absence or presence of 50 ng/ml insulin-like growth factor (IGF)-I. Purified porcine FSH (450 ng/ml) added together with IGF-I marginally increased (3)H incorporation in MGC relative to IGF-I alone but dramatically decreased incorporation in COC sixfold. Conversely, mean progesterone production in the presence of IGF-I + FSH was 13-fold higher from MGC than from COC, confirming a distinctive phenotype of cumulus cells. However, this phenotype was found to be dependent on the presence of the oocyte, as microsurgical removal of the oocyte (oocytectomy) resulted in an 11-fold decrease in [(3)H]thymidine incorporation in cumulus cells treated with IGF-I, elimination of the inhibitory effect of FSH on IGF-I-stimulated DNA synthesis, and led to a 2-fold increase in progesterone production in medium with IGF-I and FSH. All of these markers were completely restored to COC levels when oocytectomized complexes were cocultured with denuded oocytes (DO) at a concentration of 0.5 oocytes/microl, demonstrating that oocytes secrete a soluble factor(s) that promotes growth and attenuates cumulus cell progesterone secretion. In the presence of IGF-I, [(3)H]thymidine incorporation in MGC increased ninefold above control levels with the addition of DO. The addition of FSH to IGF-I-increased (3)H counts in MGC, however, led to a decrease in counts in MGC + DO as is also observed in COC. Furthermore, progesterone production was halved when DO were added to MGC cultures, most notably in the presence of IGF-I and/or FSH. These results provide further evidence that MGC and cumulus cells have distinctive phenotypes and that the oocyte is responsible for some of the characteristic features of cumulus cells. Bovine oocytes secrete a soluble factor(s) that simultaneously promotes growth and attenuates steroidogenesis in follicular somatic cells.

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“…GM-CSF is an essential cytokine for normal reproduction, with defects in Csf2 2/2 mice ranging from altered ovarian function (63,64), compromised preimplantation embryo development (65), dysregulated placental morphogenesis (16,66), and increased incidence of fetal growth restriction and death in the late gestation and perinatal period (16,17). The present study suggests that one potential cause for these reproductive anomalies might be failure to establish an optimal T cell response to pregnancy, due to impaired presentation of reproductive Ags to the T cell repertoire.…”

Section: Cd11cmentioning

confidence: 99%

GM-CSF Is an Essential Regulator of T Cell Activation Competence in Uterine Dendritic Cells during Early Pregnancy in Mice

Moldenhauer

Keenihan

Hayball

et al. 2010

The Journal of Immunology

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Uterine dendritic cells (DCs) are critical for activating the T cell response mediating maternal immune tolerance of the semiallogeneicfetus. GM-CSF (CSF2), a known regulator of DCs, is synthesized by uterine epithelial cells during induction of tolerance in early pregnancy. To investigate the role of GM-CSF in regulating uterine DCs and macrophages, Csf2-null mutant and wild-type mice were evaluated at estrus, and in the periconceptual and peri-implantation periods. Immunohistochemistry showed no effect of GM-CSF deficiency on numbers of uterine CD11c+ cells and F4/80+ macrophages at estrus or on days 0.5 and 3.5 postcoitum, but MHC class II+ and class A scavenger receptor+ cells were fewer. Flow cytometry revealed reduced CD80 and CD86 expression by uterine CD11c+ cells and reduced MHC class II in both CD11c+ and F4/80+ cells from GM-CSF–deficient mice. CD80 and CD86 were induced in Csf2−/− uterine CD11c+ cells by culture with GM-CSF. Substantially reduced ability to activate both CD4+ and CD8+ T cells in vivo was evident after delivery of OVA Ag by mating with Act-mOVA males or transcervical administration of OVA peptides. This study shows that GM-CSF regulates the efficiency with which uterine DCs and macrophages activate T cells, and it is essential for optimal MHC class II- and class I-mediated indirect presentation of reproductive Ags. Insufficient GM-CSF may impair generation of T cell-mediated immune tolerance at the outset of pregnancy and may contribute to the altered DC profile and dysregulated T cell tolerance evident in infertility, miscarriage, and preeclampsia.

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Effect of granulocyte-macrophage colony-stimulating factor deficiency on ovarian follicular cell function

Cited by 12 publications

References 22 publications

Granulocyte-Macrophage Colony-Stimulating Factor Promotes Glucose Transport and Blastomere Viability in Murine Preimplantation Embryos1

Granulocyte-Macrophage Colony-Stimulating Factor Promotes Glucose Transport and Blastomere Viability in Murine Preimplantation Embryos1

Oocyte-Secreted Factor(s) Determine Functional Differences Between Bovine Mural Granulosa Cells and Cumulus Cells1

GM-CSF Is an Essential Regulator of T Cell Activation Competence in Uterine Dendritic Cells during Early Pregnancy in Mice

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