Stromal cell-derived factor-1 (SDF-1, also called PBSF and CXCL12) is a member of chemokines, a family of structurally related chemoattractive cytokines. SDF-1 and its primary physiologic receptor CXCR4 have multiple essential functions in development including colonization of bone marrow by hematopoietic cells and neuron localization within cerebellum during embryogenesis as well as B lymphopoiesis and cardiovasculogenesis.
Depending on what properties were being studied, this molecule has been called neuropeptide Y receptor Y3, fusin, and leukocyte-derived 7-transmembrane-domain receptor, among various designations.
NCBI Summary:
This gene encodes a CXC chemokine receptor specific for stromal cell-derived factor-1. The protein has 7 transmembrane regions and is located on the cell surface. It acts with the CD4 protein to support HIV entry into cells and is also highly expressed in breast cancer cells. Mutations in this gene have been associated with WHIM (warts, hypogammaglobulinemia, infections, and myelokathexis) syndrome. Alternate transcriptional splice variants, encoding different isoforms, have been characterized. [provided by RefSeq, Jul 2008]
The CXCL12-CXCR4 signaling promotes oocyte maturation by regulating cumulus expansion in sheep. Zhang RN et al. (2017) Gonadotropins and growth factors synergistically regulate folliculogenesis and oocyte development. C-X-C motif chemokine 12 (CXCL12) and its receptor CXCR4 are expressed in ovaries of sheep, cattle and other species, however, roles of this multifunctional signal axis in oocyte maturation are not defined. Using sheep as a model, we examined the expression patterns and functions of the CXCL12-CXCR4 axis during oocyte maturation. CXCL12 and CXCR4 mRNA and protein were present in oocytes and granulosa cells. Relative abundance of CXCR4 transcript was controlled by epidermal growth factor (EGF). Transient inhibition of CXCR4 suppressed oocyte nuclear maturation while supplementing recombination CXCL12 significantly increased percent of oocyte undergone metaphase I phase. Inhibition of CXCR4 function decreased cumulus expansion growth rate. Furthermore, granulosa cell migration was impaired and expression of hyaluronan synthase 2 (HAS2) and hyaluronan binding protein tumor necrosis factor-alpha-induced protein 6 (TNFAIP6) were downregulated by CXCR4 inhibition. These findings revealed a novel role of the CXCL12-CXCR4 signaling in oocyte development in sheep.//////////////////
The expression of CXCR4 is induced by the LH surge and mediated by progesterone receptors in human preovulatory granulosa cells. Choi Y et al. (2017) The chemokine CXC Motif Ligand 12 (CXCL12) and its cognate receptor, CXCR4, have been implicated in the ovulatory process in various animal models. However, little is known about the expression and regulation of CXCL12 and CXCR4 and their functions during the ovulatory period in the human ovary. In the present study, we characterized the expression patterns of CXCL12 and CXCR4 in preovulatory follicles collected before the LH surge and at defined hours after hCG administration in women with the regular menstrual cycle. The levels of mRNA and protein for CXCR4 were increased in granulosa cells of late ovulatory follicles, whereas CXCL12 expression was constant in follicles throughout the ovulatory period. Both CXCR4 and CXCL12 were localized to a subset of leukocytes around and inside the vasculature of human preovulatory follicles. Using a human granulosa cell culture model, the regulatory mechanisms and functions of CXCL12 and CXCR4 expression were investigated. hCG stimulated CXCR4 expression, whereas CXCL12 expression was not affected, mimicking in vivo expression patterns. Both RU486 (progesterone receptor antagonist) and CoCl2 (HIFs activator) blocked the hCG-induced increase in CXCR4 expression, whereas AG1478 (EGFR inhibitor) had no effect. The treatment with CXCL12 had no effect on granulosa cell viability but decreased hCG-stimulated CXCR4 expression. In conclusion, the present data suggest that the CXCL12/CXCR4 system is present in preovulatory follicular cells as well as leukocytes in ovulatory follicles and may play a role(s) in the LH surge-induced follicular changes and infiltration of leukocytes during the ovulatory period in humans.//////////////////
CXCR4/SDF1 interaction inhibits the primordial to primary follicle transition in the neonatal mouse ovary. Holt JE et al. The molecular mechanisms behind the entry of the primordial follicle into the growing follicle pool remain poorly understood. To investigate this process further, a microarray-based comparison was undertaken between 2-day postpartum mouse ovaries consisting of primordial follicles/naked oocytes only and those with both primordial follicles and newly activated follicles (7-day postpartum). Gene candidates identified included the chemoattractive cytokine stromal derived factor-1 (SDF1) and its receptor CXCR4. SDF1 and CXCR4 have been implicated in a variety of physiological processes including the migration of embryonic germ cells to the gonads. SDF1-alpha expression increased with the developmental stage of the follicle. Embryonic expression was found to be dichotomous post-germ cell migration, with low expression in the female. Immunohistochemical studies nonetheless indicate that the autocrine pattern of expression ligand and receptor begins during embryonic life. Addition of recombinant SDF1-alpha to neonatal mouse ovaries in vitro resulted in significantly higher follicle densities than for control ovaries. TUNEL analysis indicated no detectable difference in populations of apoptotic cells of treated or control ovaries. Treated ovaries also contained a significantly lower percentage of activated follicles as determined by measurement of oocyte diameter and morphological analysis. Treatment of cultured ovaries with an inhibitor of SDF1-alpha, AMD3100, ablated the effect of SDF1-alpha. By retaining follicles in an unactivated state, SDF1/CXCR4 signaling may play an important role in maintaining the size and longevity of the primordial follicle pool.
Expression regulated by
LH
Comment
Expression and regulation of stromal cell-derived factor-1 (SDF1) and chemokine CXC motif receptor 4 (CXCR4) in equine and bovine preovulatory follicles. Sayasith K 2014 et al.
The interaction between stromal cell-derived factor-1 (SDF1) and chemokine CXC motif receptor 4 (CXCR4) has been implicated in leukocyte attraction, tissue remodeling and angiogenesis. The objective of the present study was to characterize the expression and regulation of SDF1 and CXCR4 in equine follicles during the ovulatory process. Equine preovulatory follicles were isolated during estrus 0-39h after hCG treatment. Follicle wall preparations (theca interna with attached granulosa cells) and isolated preparations of granulosa cells and theca interna were obtained, and total RNA extracts were analyzed by RT-PCR/Southern blot. Results showed that levels of CXCR4 transcripts were induced by hCG in follicles at 36h post-hCG (P<0.05 vs 0h), with the induction observed in both granulosa and theca cells. Immunoblotting and immunohistochemical analyses confirmed an increase in CXCR4 protein in follicles after hCG treatment. In contrast, levels of SDF1 transcripts were very low in granulosa cells but high in theca interna cells throughout most of the ovulatory period. Studies in vivo performed with bovine preovulatory follicles collected 0-24h post-hCG revealed a marked and significant up-regulation of CXCR4 transcripts after hCG (P<0.05), as observed in equine follicles. A similar pattern of CXCR4 mRNA up-regulation was observed in cultures of bovine granulosa cells treated with forskolin (P<0.05). This forskolin-dependent induction of CXCR4 mRNA was suppressed by co-treatment with inhibitors of PKA, ERK1/2 and EGFR, and by the progesterone receptor antagonist RU486 (P<0.05), underscoring the contribution of multiple signaling pathways. In complementary studies, treatment of bovine granulosa cells with EGF or the hypoxia mimetic cobalt chloride significantly increased CXCR4 transcript levels, whereas co-treatment with forskolin and a CXCR4 antagonist repressed the expression of several ovulation-related genes. Collectively, this study describes for the first time the gonadotropin-dependent up-regulation of CXCR4 transcript in ovarian follicles of large monoovulatory species, provides some insights into the regulation of CXCR4 gene expression in granulosa cells, and identifies a potential link between follicular SDF1/CXCR4 activation and the regulation of ovulation-related genes.
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Ovarian localization
Cumulus, Granulosa, Theca, ovarian tumor
Comment
Scotton CJ, et al
investigated the possibility that chemokine gradients influence migration of human ovarian epithelial tumor cells. Of 14 chemokine receptors investigated, only CXCR4 was expressed on ovarian cancer cells. CXCR4 mRNA localized to a subpopulation of tumor cells in ovarian cancer biopsies. Ovarian cancer cell lines and cells freshly isolated from ascites expressed CXCR4 protein. The CXCR4 ligand, CXCL12, was found in ascites from 63 patients. CXCL12 elicited intracellular calcium flux and directed migration and changes in integrin expression in ovarian cancer cells. CXCR4 may influence cell migration in the peritoneum, a major route for ovarian cancer spread, and could be a therapeutic target.
Gene expression profiles of cumulus cell oocyte complexes during ovulation reveal cumulus cells express neuronal and immune-related genes: does this expand their role in the ovulation process? Hernandez-Gonzalez I et al. Ovulation is a complex process initiated by the preovulatory LH surge, characterized by cumulus oocyte complex (COC) expansion and completed by the release of a mature oocyte. Although many ovarian genes that impact ovulation have been identified, we hypothesized that genes selectively expressed in COCs would be overlooked by approaches using whole ovary or granulosa cell samples. RNA isolated from COCs collected from preovulatory follicles of equine chorionic gonadotropin (CG) primed mice and at selected times after human CG treatment was subjected to microarray analyses and results confirmed by RT-PCR analyses, Western blotting, and immunofluorescent studies. A remarkable number of genes were up-regulated in COCs including Areg, Ereg, and Btc. Several genes selectively expressed in cumulus cells compared with granulosa cells were related to neuronal (Mbp, Tnc, Nts) or immune (Alcam, Pdcd1, Cd34, Cd52, and Cxcr4) cell function. In addition to Sfrp2, other members of the Wnt/Fzd family (Sfrp4, Fdz1 and Fdz2) were expressed in COCs. Thus, there is a cumulus cell-specific, terminal differentiation process. Furthermore, immunofluorescent analyses documented that cumulus cells are highly mitotic for 4-8 h after human CG and then cease dividing in association with reduced levels of Ccnd2 mRNA. Other down-regulated genes included: Cyp19a1, Fshr, Inhb, and the oocyte factors Zp1-3 and Gja4. In summary, the vast number of matrix, neuronal, and especially immune cell-related genes identified by the gene- profiling data of COCs constitutes strong and novel evidence that cumulus cells possess a repertoire of immune functions that could be far greater than simply mediating an inflammatory-like response.
Differential gene expression in cumulus cells as a prognostic indicator of embryo viability: a microarray analysis. van Montfoort AP et al. Besides the established selection criteria based on embryo morphology and blastomere number, new parameters for embryo viability are needed to improve the clinical outcome of IVF and more particular of elective single embryo transfer (eSET). Genome-wide gene expression in cumulus cells was studied, since these cells surround the oocyte inside the follicle and therefore possibly reflect oocyte developmental potential. Early cleavage (EC) was chosen as a parameter for embryo viability. Gene expression in cumulus cells from eight oocytes resulting in an EC embryo (EC-CC; n=8) and from eight oocytes resulting in a non-EC (NEC) embryo (NEC-CC; n=8) was analysed using microarrays (n=16). A total of 611 genes were differentially expressed (P < 0.01), mainly involved in cell cycle, angiogenesis, apoptosis, epidermal growth factor, fibroblast growth factor and platelet-derived growth factor signalling, general vesicle transport and chemokine and cytokine signalling. Of the 25 selected differentially expressed genes analysed by quantitative real-time PCR (qRT-PCR) 15 (60%) genes could be validated in the original samples. Of these 8 (53%) could also be validated in 24 (12-EC-CC and 12 NEC-CC) extra independent samples. The most differentially expressed genes among these were CCND2, CXCR4 , GPX3 , CTNND1 DHCR7 , DVL3 , HSPB1 and TRIM28 , which probably point to hypoxic conditions or a delayed oocyte maturation in NEC-CC samples. This opens up perspectives for new molecular embryo or oocyte selection parameters which might also be useful in countries where the selection has to be made at the oocyte stage before fertilization instead of at the embryonic stage.
Follicle stages
Comment
Phenotypes
Mutations
2 mutations
Species: None
Mutation name: None
type: null mutation fertility: infertile - ovarian defect Comment:Knaut H, et al reported that a zebrafish homologue of the chemokine receptor Cxcr4 is a
germ-cell guidance receptor.
Germ cells preserve an individual's genetic information and transmit it to the next
generation. Early in development germ cells are set aside and undergo a specialized
developmental programme, a hallmark of which is the migration from their site of
origin to the future gonad. In Drosophila, several factors have been identified that
control germ-cell migration to their target tissues; however, the germ-cell
chemoattractant or its receptor have remained unknown. Here the athors apply genetics and
in vivo imaging to show that odysseus, a zebrafish homologue of the
G-protein-coupled chemokine receptor Cxcr4, is required specifically in germ cells
for their chemotaxis. odysseus mutant germ cells are able to activate the migratory
programme, but fail to undergo directed migration towards their target tissue,
resulting in randomly dispersed germ cells. SDF-1, the presumptive cognate ligand
for Cxcr4, shows a similar loss-of-function phenotype and can recruit germ cells to
ectopic sites in the embryo, thus identifying a vertebrate ligand-receptor pair guiding
migratory germ cells at all stages of migration towards their target.
Species: mouse
Mutation name: None
type: null mutation fertility: subfertile Comment:Toshiaki Ara et al reported impaired colonization of the gonads by primordial germ cells in mice lacking a chemokine, stromal cell-derived factor-1 (SDF-1) .
Primordial germ cells (PGCs) are the founders of sperm or oocytes. PGCs migrate through the tissues of the embryos and colonize the gonads during development. However, the cytokines essential for colonization of the gonads by PGCs in mammals remain unclear. PGCs have cell-surface expression of CXCR4 and that, in SDF-1 / mice, PGCs undergo directed migration through tissues of embryos, but the numbers of PGCs in the gonads are significantly reduced. The proliferation of PGCs within the gonads seems normal in the mutant mice. These findings reveal the essential role for SDF-1 in murine PGC development likely by controlling colonization of the gonads by PGCs.