Member Of Fibroblast Growth Factor Family Research Articles

Cloning, Expression and Purification of Mouse Fibroblast Growth Factor-21 and Its Function in Adipocyte Glucose Metabolism*

Fibroblast growth factor (FGF)-21 is a new member of FGF family. Recently, it is discovered as a potent glucose regulator and a potential drug candidate for treatment of type 2 diabetes mellitus. However the mechanism of action is not known. Mouse FGF-21(mFGF-21) is the best model for study of the mechanism of action of human counterpart, but function of mFGF-21 has not been reported. The aim of this paper is to study the function of mFGF-21 for glucose regulation. For efficiently production of bioactive FGF-21, a Sumo-His expression vector for efficient expression of soluble recombinant proteins was constructed. A hydroxylamine cleavage site was used to substitute the Sumo protease cleavage site for economic purpose. The mFGF-21 cDNA was cloned from mouse liver and sub-cloned into the Sumo-His expression vector. The mFGF-21 was stably expressed in Rosetta host cells, the expressed products were water-soluble. The Sumo-His-mFGF fusion protein was purified by Ni-NTA Column and subsequently subjected to cleavage with hydroxylamine solution to remove the Sumo-His tag; the mature mFGF-21 was dialyzed against 20 mmol/L Tris buffer (pH 8.0) for re-nature. The mature protein with high purity was obtained. The sequencing result indicated that the mature protein consisted of 182 amino acids. SDS-PAGE gel analysis showed that the protein molecular mass was 24 ku, which was recognized by the polyclonal antibody against FGF-21. The amino acid sequence of mFGF-21 had 80% homology with that of human counterpart which was consistent with the published sequence. To examine the glucose regulation activity of mFGF-21, 3T3-L1 pre-adipocytes were differentiated into adipocytes, glucose up-take activity of mFGF-21 was examined by Glucose Oxidase and Peroxidase (GOD-POD) assay at the 14th day after differentiation when 90% of preadipocytes were differentiated into adipocytes. To validate the glucose uptake assay system commercial available human insulin was used to test the assay system. The result showed that insulin could stimulate glucose uptake of 3T3L1 adipocytes in dose-dependent manner, suggesting the glucose-uptake assay system is valid. mFGF-21 was subsequently tested in this system, the result showed that like human FGF-21 and insulin, mouse FGF-21 could also stimulate glucose uptake of 3T3-L1 adipocytes in dose-dependent manner. To examine time of action of mFGF-21, 1000 nmol/L of mFGF-21 were used to treat differentiated adipocytes for 1, 4, 8 and 12 h respectively, together with the same concentration of insulin and BSA as a positive and negative control. Glucose consumption of the medium was examined. The result showed that both insulin and mFGF-21 had tendency to increase glucose up-take of adipocytes with increment of action time. However, mFGF-21 was more potent and showed stronger time-dependent action, which was in agreement with the function of human FGF-21 as reported previously. BSA did not show any glucose uptake activity as expected. It was conclude that mouse FGF-21 is similar to human FGF-21 and possesses strong bioactivity for glucose homeostasis in 3T3-L1 adipocytes, and therefore can be used as a model for study mechanism of action of human FGF-21. The function of mFGF-21 in glucose metabolism at animal level is remained to be studied.

Early Control of PTH and FGF23 in Normophosphatemic CKD Patients

Levels of parathyroid hormone (PTH) and the phosphaturic hormone FGF23, a fibroblast growth factor (FGF) family member, increase early in chronic kidney disease (CKD) before the occurrence of hyperphosphatemia. This short-term 6-wk dose titration study evaluated the effect of two phosphate binders on PTH and FGF23 levels in patients with CKD stages 3 to 4. Patients were randomized to receive over a 6-wk period either calcium acetate (n = 19) or sevelamer hydrochloride (n = 21). At baseline, patients presented with elevated fractional excretion of phosphate, serum PTH, and FGF23. During treatment with both phosphate binders there was a progressive decline in serum PTH and urinary phosphate, but no change in serum calcium or serum phosphate. Significant changes were observed for FGF23 only in sevelamer-treated patients. This study confirms the positive effects of early prescription of phosphate binders on PTH control. Prospective and long-term studies are necessary to confirm the effects of sevelamer on serum FGF23 and the benefits of this decrease on outcomes.

Glypican-1 controls brain size through regulation of fibroblast growth factor signaling in early neurogenesis

BackgroundCell surface heparan sulfate proteoglycans (HSPGs) act as co-receptors for multiple families of growth factors that regulate animal cell proliferation, differentiation and patterning. Elimination of heparan sulfate during brain development is known to produce severe structural abnormalities. Here we investigate the developmental role played by one particular HSPG, glypican-1 (Gpc1), which is especially abundant on neuronal cell membranes, and is the major HSPG of the adult rodent brain.ResultsMice with a null mutation in Gpc1 were generated and found to be viable and fertile. The major phenotype associated with Gpc1 loss is a highly significant reduction in brain size, with only subtle effects on brain patterning (confined to the anterior cerebellum). The brain size difference emerges very early during neurogenesis (between embryonic days 8.5 and 9.5), and remains roughly constant throughout development and adulthood. By examining markers of different signaling pathways, and the differentiation behaviors of cells in the early embryonic brain, we infer that Gpc1-/- phenotypes most likely result from a transient reduction in fibroblast growth factor (FGF) signaling. Through the analysis of compound mutants, we provide strong evidence that Fgf17 is the FGF family member through which Gpc1 controls brain size.ConclusionThese data add to a growing literature that implicates the glypican family of HSPGs in organ size control. They also argue that, among heparan sulfate-dependent signaling molecules, FGFs are disproportionately sensitive to loss of HSPGs. Finally, because heterozygous Gpc1 mutant mice were found to have brain sizes half-way between homozygous and wild type, the data imply that endogenous HSPG levels quantitatively control growth factor signaling, a finding that is both novel and relevant to the general question of how the activities of co-receptors are exploited during development.

The Insulin-Like Growth Factor (IGF) Receptor Type 1 (IGF1R) as an Essential Component of the Signalling Network Regulating Neurogenesis

The insulin-like growth factor receptor type 1 (IGF1R) signalling pathway is activated in the mammalian nervous system from early developmental stages. Its major effect on developing neural cells is to promote their growth and survival. This pathway can integrate its action with signalling pathways of growth and morphogenetic factors that induce cell fate specification and selective expansion of specified neural cell subsets. This suggests that during developmental and adult neurogenesis cellular responses to many signalling factors, including ligands of Notch, sonic hedgehog, fibroblast growth factor family members, ligands of the epidermal growth factor receptor, bone morphogenetic proteins and Wingless and Int-1, may be modified by co-activation of the IGF1R. Modulation of cell migration is another possible role that IGF1R activation may play in neurogenesis. Here, I briefly overview neurogenesis and discuss a role for IGF1R-mediated signalling in the developing and mature nervous system with emphasis on crosstalk between the signalling pathways of the IGF1R and other factors regulating neural cell development and migration. Studies on neural as well as on non-neural cells are highlighted because it may be interesting to test in neurogenic paradigms some of the models based on the information obtained in studies on non-neural cell types.

Comparison of Expression Profiles of Several Fibroblast Growth Factor Receptors in the Mouse Jejunum: Suggestive Evidence for a Differential Radioprotective Effect among Major FGF Family Members and the Potency of FGF1

Several members of the fibroblast growth factor (FGF) family have the potential to protect the intestine against the side effects of radiation therapy. FGF1 is capable of signaling through all subtypes of FGF receptors (FGFRs), whereas FGF7 and FGF10 activate only the epithelial-specific subtype, FGFR2IIIb (FGFR2b). The present study compared the protective activity of FGF1, FGF7 and FGF10 and examined the profiles of FGFR expression in the jejunum of BALB/c mice given total-body irradiation (TBI) with gamma rays. TBI caused drastic increases in FGFR1-4 transcript levels in the jejunum. However, FGFR2b protein temporarily decreased at 12 and 24 h after irradiation. FGF1 pretreatment minimized the number of apoptotic cells in jejunal crypts at 16 and 24 h after irradiation and increased crypt survival most effectively. In addition, pretreatment with FGF7 or FGF10 decreased FGFR1 transcript levels. The greater effectiveness of FGF1 to enhance crypt survival was also observed even when each FGF was administered 1 h after irradiation. These findings indicate that FGF1 is more potent than FGF7 or FGF10 for protection of the intestine against radiation exposure and suggest that the profiles of FGFR expression in the intestine favor the FGF1 signaling pathway before and during the initial period after irradiation.

Expression and possible role of fibroblast growth factor family members in porcine antral follicles during final maturation

The aim of this study was to investigate the possible participation of fibroblast growth factor (FGF) family members (FGF1, FGF2 and FGF7 and their receptors) in porcine follicles (polyovulatory species) under special consideration for FGF2 during final growth. A classification of follicles was done by size and follicular fluid content of oestradiol-17beta, progesterone and prostaglandin F2alpha. The mRNA expression of examined factors was analysed by real-time PCR. The hormone concentration was estimated by enzyme immunoassay, protein characterisation by western blotting and localisation by immunohistochemistry. Follicle tissue separated in theca interna and granulosa cells was extracted and tested for mRNA of FGF1, FGF2, FGF7 and receptors (FGFR1IIIc, FGFRIIIb and FGFR2IIIc). Additionally, the mRNA expression of FSHR, LHR and aromatase cytochrome P450 for further characterisation of follicles was analysed. Significantly, higher FGF2 protein levels were measured in stroma when compared with total follicle or corpus luteum tissue. This result was confirmed by western blot with two strong bands. Immunological localisation of FGF2 only in stroma (fibroblasts) confirms the protein measurements. The results show a clear difference for FGF2 protein expression during final growth of follicles if monovulatory (bovine) and polyovulatory (porcine) species are compared. FGF2 protein in porcine ovary may be (due to localisation and concentration in stroma) important for support of angiogenesis of more follicles (polyovulatory species) and not of a single follicle like in cows.

Novel Cross-Talk between Three Cardiovascular Regulators: Thrombin Cleavage Fragment of Jagged1 Induces Fibroblast Growth Factor 1 Expression and Release

Angiogenesis is controlled by several regulatory mechanisms, including the Notch and fibroblast growth factor (FGF) signaling pathways. FGF1, a prototype member of FGF family, lacks a signal peptide and is released through an endoplasmic reticulum-Golgi-independent mechanism. A soluble extracellular domain of the Notch ligand Jagged1 (sJ1) inhibits Notch signaling and induces FGF1 release. Thrombin, a key protease of the blood coagulation cascade and a potent inducer of angiogenesis, stimulates rapid FGF1 release through a mechanism dependent on the major thrombin receptor protease-activated receptor (PAR) 1. This study demonstrates that thrombin cleaves Jagged1 in its extracellular domain. The sJ1 form produced as a result of thrombin cleavage inhibits Notch-mediated CBF1/Suppressor of Hairless [(Su(H)]/Lag-1-dependent transcription and induces FGF1 expression and release. The overexpression of Jagged1 in PAR1 null cells results in a rapid thrombin-induced export of FGF1. These data demonstrate the existence of novel cross-talk between thrombin, FGF, and Notch signaling pathways, which play important roles in vascular formation and remodeling.

FGF Signaling Preserves the Integrity of Endothelial Adherens Junctions

Fibroblast growth factor (FGF)-activated signaling regulates an array of cellular processes ranging from embryonic development to tissue repair. A recent paper by Murakami et al. identifies a potentially important role for FGF signaling in maintenance of endothelial barrier homeostasis through the regulation of adherens junctions.

Possible Role of Fibroblast Growth Factor (FGF) Family Members in Porcine Antral Follicles During Final Follicle Maturation.

Possible Role of Fibroblast Growth Factor (FGF) Family Members in Porcine Antral Follicles During Final Follicle Maturation.

Physiological Regulation and Disorders of Phosphate Metabolism -Pivotal Role of Fibroblast Growth Factor 23-

Fibroblast growth factor (FGF) 23 has been identified as the last member of FGF family. FGF23 reduces serum phosphate level by suppressing proximal tubular phosphate reabsorption and intestinal phosphate absorption. FGF23 is produced by bone and acts on the kidney through a specific receptor system which is composed of Klotho and certain subtypes of FGF receptors. Excess actions of FGF23 cause several hypophosphatemic diseases characterized by impaired renal phosphate reabsorption and rickets/osteomalacia. In contrast, deficient actions of FGF23 result in hyperphosphatemic tumoral calcinosis with enhanced renal phosphate reabsorption. These results indicate that FGF23 works as a hormone to regulate the serum phosphate level.

Co-receptor Requirements for Fibroblast Growth Factor-19 Signaling

FGF19 is a unique member of the fibroblast growth factor (FGF) family of secreted proteins that regulates bile acid homeostasis and metabolic state in an endocrine fashion. Here we investigate the cell surface receptors required for signaling by FGF19. We show that betaKlotho, a single-pass transmembrane protein highly expressed in liver and fat, induced ERK1/2 phosphorylation in response to FGF19 treatment and significantly increased the interactions between FGF19 and FGFR4. Interestingly, our results show that alphaKlotho, another Klotho family protein related to betaKlotho, also induced ERK1/2 phosphorylation in response to FGF19 treatment and increased FGF19-FGFR4 interactions in vitro, similar to the effects of betaKlotho. In addition, heparin further enhanced the effects of both alphaKlotho and betaKlotho in FGF19 signaling and interaction experiments. These results suggest that a functional FGF19 receptor may consist of FGF receptor (FGFR) and heparan sulfate complexed with either alphaKlotho or betaKlotho.

Liver-specific Activities of FGF19 Require Klotho beta

Hepatocyte function is regulated by members of the fibroblast growth factor (FGF) family of proteins, but little is known about the specific molecular mechanisms of this endocrine pathway. FGF19 regulates bile acid homeostasis and gall bladder filling; FGF19 binds only to FGF receptor 4 (FGFR4), but its liver-specific activity cannot be explained solely by the distribution of this receptor. Although it has been suggested that Klotho beta (KLB) may have a role in mediating FGF19 activity, we have provided for the first time definitive evidence that KLB is required for FGF19 binding to FGFR4, intracellular signaling, and downstream modulation of gene expression. We have shown that FGFR4 is widely distributed in mouse, whereas KLB distribution is more restricted. Liver was the only organ in which both genes were abundantly expressed. We show that in mice, FGF19 injection triggers liver-specific induction of c-Fos and repression of CYP7A1. The tissue-specific activity of FGF19 supports the unique intersection of KLB and FGFR4 distribution in liver. These studies define KLB as a novel FGFR4 coreceptor required for FGF19 liver specific functions.

Profiling the Sulfation Specificities of Glycosaminoglycan Interactions with Growth Factors and Chemotactic Proteins Using Microarrays

We report a carbohydrate microarray-based approach for the rapid, facile analysis of glycosaminoglycan-protein interactions. The key structural determinants responsible for protein binding, such as sulfate groups that participate in the interactions, were elucidated. Specificities were also readily compared across protein families or functional classes, and comparisons among glycosaminoglycan subclasses provided a more comprehensive understanding of protein specificity. To validate the approach, we showed that fibroblast growth factor family members have distinct sulfation preferences. We also demonstrated that heparan sulfate and chondroitin sulfate interact in a sulfation-dependent manner with various axon guidance proteins, including slit2, netrin1, ephrinA1, ephrinA5, and semaphorin5B. We anticipate that these microarrays will accelerate the discovery of glycosaminoglycan-binding proteins and provide a deeper understanding of their roles in regulating diverse biological processes.

Progressive mRNA decay establishes an mkp3 expression gradient in the chick limb bud

The apical ectodermal ridge (AER) controls limb outgrowth and patterning, such that its removal causes changes in mesodermal gene expression, cell death and limb truncation. Fibroblast growth factor (FGF) family members are expressed in the AER and can rescue limb bud outgrowth after AER removal. Cells localized underneath the AER are maintained in an undifferentiated state by the FGFs produced by the AER. MAPK phosphatase 3 ( mkp3) is a downstream effector of FGF8 signalling during limb bud development and is expressed in the distal limb mesenchyme. The present work evidences a gradient of mkp3 transcripts along the chick limb bud, in a distal to proximal direction. mkp3 transcription occurs only in the most distal limb bud cells and its mRNA gradient throughout the limb results from progressive mRNA decay. We show that FGF8-soaked beads induce ectopic mkp3 expression, indicating that AER-derived FGF8 protein may activate mkp3 in the distal mesenchyme.

73 POSTER Pharmacokinetic characterization of BIBF 1120, an orally active triple angiokinase inhibitor (VEGFR, PDGFR, FGFR) in advanced cancer patients

Fibroblast growth factors (FGFs) are a family of pleiotropic factors produced by stromal and parenchymal tumor cells. Even though FGFs have been firstly characterized as angiogenic factors, they exert autocrine and paracrine functions not only on endothelial cells but also on tumor cells and other stromal components. Thus, the FGF/FGF receptor (FGFR) pathway may represent a key player in tumor growth by regulating the complex cross-talk between stromal and tumor compartments.The ligand dependent or independent activation of the FGF/FGFR system by gene upregulation, oncogenic mutation or amplification occurs in a variety of human tumors and is implicated in various key steps of tumor growth and progression. In addition, FGF/FGFR activation has been described as a mechanism of tumor escape in response to antiangiogenic/anti-VEGF therapies.Experimental and clinical evidences provide a compelling biologic rationale for the development of anti-FGF/FGFR targeting agents in cancer therapy. However, the development of drugs specifically targeting the FGF/FGFR pathway proved to be difficult, also due to the high redundancy and pleiotropic effects of FGF and FGFR family members. On the other hand, the possibility to develop ⿿two-compartment⿿ targeting agents endowed with both antiangiogenic and antitumor activities remains promising.Here we will review the preclinical and clinical approaches and potential therapeutics currently available to block the FGF/FGFR system in human cancer.

Fibroblast Growth Factors, Fibroblast Growth Factor Receptors, Diseases, and Drugs

Maintenance of endothelial cells (ECs), the building blocks of the vascular tree, is a presumed function of fibroblast growth factors (FGFs). In particular, the two prototypic members of FGF family, namely FGF1 and FGF2, due to their potent mitogenic and pro-migratory activities, have the ability to induce metabolic and phenotypic changes in ECs that are required to stimulate angiogenesis. In addition to FGF1 and FGF2, 23 other members of the FGF family have since been identified and characterized and they are reviewed in relation to their disease pathology. Particular emphasis is given to the biology of the FGFs and FGFRs on how they mediate the onset of angiogenesis. The focus of the present review is to survey what is known about the role of the currently identified FGFs and their four high affinity tyrosine kinase receptors in diseases and the angiogenesis-targeted drugs currently in clinical trials. Some new and promising patented drugs that target the angiogenic pathway are discussed. Examination of the currently patented drugs may identify more potent and specific regulators of FGF/FGFR signaling system for treatment of tumor angiogenesis in clinical settings. Additionally, novel drug development strategies are highlighted and reviewed.

FGF Ligand Family mRNA Expression Profile for Mouse Preimplantation Embryos, Early Gestation Human Placenta, and Mouse Trophoblast Stem Cells

Signaling by fibroblast growth factor (FGF) is essential is for trophoblast stem (TS) cells and preimplantation embryos. FGF4 provides essential signaling, but the expression of the complete set of 23 FGF family members has not been analyzed. Here, semi-quantitative RT-PCR and microarray analyses were used to define expression of all FGF ligand mRNA. RT-PCR was done for developmentally important FGF subfamilies, FGF10/FGF22 and FGF8/FGF17/FGF18 as well as FGF11. FGF4 and FGF18 are detected at highest levels by RT-PCR and microarrays. FGF10 was detected at low levels in both assays. FGF11 was detected at moderate levels by microarray, but not by RT-PCR. FGF17 was detected at low levels by array and moderate levels by RT-PCR. FGF8 and FGF22 were detected by RT-PCR, but not by microarrays during late cleavage divisions. FGF8, FGF5, and FGF9 were detected in the oocyte by microarray. FGF2, FGF3, and FGF7 were not detected by RT-PCR or microarrays and FGF13, FGF14, and FGF23 were not detected by microarray. Since a major role of FGF is to maintain TS cells, we tested human and mouse placental cell lines and early gestation human placenta for expression of FGF ligands. Expression in mouse TS cells was compared with preimplantation embryos, and human placental cell line expression was compared with human placenta, to infer which ligands are expressed in placental lineage vs. other cell lineages. The data suggest that human and mouse placenta share FGF18 and its high expression suggests preimplantation and early placental function.

IncreasingFgf4expression in the mouse limb bud causes polysyndactyly and rescues the skeletal defects that result from loss ofFgf8function

A major function of the limb bud apical ectodermal ridge (AER) is to produce fibroblast growth factors (FGFs) that signal to the underlying mesenchyme. Previous studies have suggested that of the four FGF genes specifically expressed in the mouse AER, Fgf8 is unique not only in its expression pattern, but also because it is the only such FGF gene that causes limb skeletal abnormalities when individually inactivated. However, when both Fgf8 and Fgf4 are simultaneously inactivated in the AER, the limb does not develop. One possible explanation for these observations is that although both of these FGF family members contribute to limb development, Fgf8 has functions that Fgf4 cannot perform. To test this hypothesis, we used a novel method to substitute Fgf4 for Fgf8 expression in the developing limb bud by concomitantly activating a conditional Fgf4 gain-of-function allele and inactivating an Fgf8 loss-of-function allele in the same cells via Cre-mediated recombination. Our data show that when Fgf4 is expressed in place of Fgf8, all of the skeletal defects caused by inactivation of Fgf8 are rescued, conclusively demonstrating that FGF4 can functionally replace FGF8 in limb skeletal development. We also show that the increase in FGF signaling that occurs when the Fgf4 gain-of-function allele is activated in a wild-type limb bud causes formation of a supernumerary posterior digit (postaxial polydactyly), as well as cutaneous syndactyly between all the digits. These data underscore the importance of controlling the level of FGF gene expression for normal limb development.

Expression of Fibroblast Growth Factors (FGF) and FGF Receptor (FGFR) in the Horse Placenta

Members of the fibroblast growth factor family have been shown to stimulate angiogenesis and cell differentiation during embryogenesis and invasive haemochorial placentation. The non‐invasive epitheliochorial horse placenta is characterized by the occurrence of specialized areolae between the microcotyledons, where secretions of endometrial glands are imbibed by the pseudostratified trophoblast cells throughout gestation. Therefore, we hypothesize that trophoblast cells may be programmed differently depending on their location and function. The influence of FGF family members during placentation in the mare was evaluated in tissues from five mares at days 110, 121, 179, 199, and 309 of gestation. Placental samples were perfusion‐fixed and paraffin‐embedded, and immunohistochemistry was performed with antibodies against FGF1 and FGF2 (which have been shown to influence cells of mesenchymal origin), FGF7 which acts on epithelial cells, and an antibody against FGFR which recognizes various receptor isoforms. FGF1 immunostaining occurred in most cells of the placenta throughout gestation, with the strongest expression in vascular structures. FGF2 protein expression differed in relation to location and stage of gestation. Trophoblast and endometrial epithelial cells in the microcotyledons showed strong nuclear expression, whereas areolar trophoblast, fetal and maternal endothelial cells, and smooth muscle cells of large allantochorionic blood vessels all showed cytoplasmic localization of FGF2. Near term, on day 309, FGF2 expression ceased in all types of cells. FGF7 immunoreactivity was observed predominantly in the nuclei of endometrial gland cells and the cytoplasm of trophoblast cells, and to a lesser extent in the endometrial epithelium. FGFR immunoreaction occurred almost exclusively in vascular cells, such as the endothelium and smooth muscle cells of large blood vessels, and staining declined towards term. The nuclear localization of FGF2 and FGF7 suggests the presence of high molecular weight isoforms, which have been shown to be involved in specific autocrine transcription processes, like activation of endometrial glands and differentiation of trophoblast cells. In contrast, the cytoplasmic localization of FGFs indicates the presence of low molecular weight isoforms. These would represent the classic FGFR binding isoforms that may be involved in angiogenesis mediated by auto‐ and paracrine mechanisms.

Fibroblast Growth Factor (FGF)-1, FGF2, FGF7 and FGF Receptors are Uniformly Expressed in Trophoblast Giant Cells During Restricted Trophoblast Invasion in Cows

The bovine placenta is characterized by a limited invasion of trophoblast giant cells (TGC). In contrast to mononuclear trophoblast cells (MTC), TGC are non-polarized cells, which migrate and fuse with single uterine epithelial cells throughout gestation. Fibroblast growth factors (FGF) were shown to be associated with the migratory activity of cells, cell differentiation and angiogenesis, and due to its localization in trophoblast cells were proposed as important regulating factors in hemochorial placentae of rodents and humans, and the (syn)epitheliochorial placenta of pig and sheep. Since migrating bovine TGC are of epithelial origin, but exhibit similarities to mesenchymal cells we hypothesize that the restricted trophoblast invasion in cattle is characterized by a specific FGF expression pattern. Therefore, the spatiotemporal expression of specific FGF factor:receptor pairs, either acting on cells of mesenchymal origin or on epithelial cells was examined in bovine placental tissues throughout gestation and prepartum by immunohistochemistry, semiquantitative RT-PCR and in situ hybridization. FGF1 protein was found in trophoblast, caruncular epithelium (CE) and stroma (CS), stroma of chorionic villi (SCV), and in fetal and maternal blood vessels. FGF2 signals dominated in maternal vascular endothelia (VE), immature TGC, and MTC, whereas staining in other cell types was clearly weaker. FGF7 protein was detected in fetal and maternal blood vessel as well as in immature TGC and MTC predominantly at the chorionic plate. FGFR immunoreaction was localized in immature TGC, MTC, and to a clearly lesser extent in CS, CE and fetal and maternal blood vessels. Mature TGC stained negatively for all examined factors and FGFR. The corresponding mRNAs specific for FGF1, -2, -7, total FGFR, and FGFR2 isoforms IIIb and IIIc were colocalized in immature TGC, whereas hybridization was substantially lower in CE and absent in CS, SCV and mature TGC throughout gestation, but switched to CS and VE immediately prepartum. Semiquantitative RT-PCR revealed higher mRNA levels for FGF1, FGFR, and FGFR2IIIc in cotyledons compared to caruncles (p<0.05), whereas it was the opposite with FGF2 (p<0.001). FGF7 and FGFR2IIIb mRNA levels did not differ between caruncles and cotyledons. Significant changes (p<0.05) of mRNA levels related to gestational age were found for FGF1 and FGFR2IIIc, but not for FGF2, -7, total FGFR, and FGFR2IIIb. The specific localization of all examined FGF family members in TGC suggests that TGC, apart from their classical function as producers of hormonal products, play other important roles in the regulation of bovine placentomal growth, differentiation and angiogenesis.