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PubMed2000

Exogenous FGF-4 can suppress anterior development in the mouse embryo during neurulation and early organogenesis.

Members of the fibroblast growth factor (FGF) family of peptide growth factors are widely expressed in the germ layer derivatives during gastrulation and early organogenesis of the mouse. We have investigated the effect of administering recombinant FGF-4 in the late-primitive streak stage embryo to test if the patterning of the body plan may be influenced by this growth factor. Shortly after FGF treatment the embryonic tissues up-regulated the expression of Brachyury and the RTK signaling regulator Spry2, suggesting that FGF signaling was activated as an immediate response to exogenous FGF. Concomitantly, Hesx1 expression was suppressed in the prospective anterior region of the embryo. After 24 h of in vitro development, embryos displayed a dosage-related suppression of forebrain morphogenesis, disruption of the midbrain-hindbrain partition, and inhibition of the differentiation of the embryonic mesoderm. Overall, development of the anterior-posterior axis in the late gastrula is sensitive to the delivery of exogenous FGF-4. The early response associated with the expression of Spry2 suggests that the later phenotype observed could be primarily related to an inhibition of the FGF signaling pathway.

Adaptor Proteins, Signal Transducing↗
PubMed2000

FGF-2 Up-regulation and proliferation of neural progenitors in the regenerating amphibian spinal cord in vivo.

Regeneration of the spinal cord occurs spontaneously in adult urodele amphibians. The key cells in this regenerative process appear to be the ependymal cells that following injury migrate and proliferate to form the ependymal tube from which the spinal cord regenerates. Very little is known about the signal(s) that initiates and maintains the proliferative response of these cells. Fibroblast growth factor 2 (FGF-2) has been shown to play a role in maintaining neural progenitor cell cycling in vitro and may be important for neuronal survival and axonal growth after injury. We have investigated its role in regeneration of the spinal cord in vivo following tail amputation in the adult salamander, Pleurodeles waltl. We show that only the low-molecular-weight form of FGF-2 is found in Pleurodeles and that in the normal cord it is expressed in a subset of neurons, but is hardly detectable in ependymal cells. Tail amputation results in induction of FGF-2 in the ependymal cells of the regenerating structure, and later in regeneration FGF-2 is up-regulated in some newborn neurons. FGF-2 pattern of expression in the ependymal tube parallels that of proliferation. Furthermore, exogenous FGF-2 significantly increases ependymal cell proliferation in vivo. Overall our results strongly support the view that one important role of FGF-2 during spinal cord regeneration in Pleurodeles is to induce proliferation of neural progenitor cells.

Amputation, Surgical↗
PubMed2000

Expression of activated MAP kinase in Xenopus laevis embryos: evaluating the roles of FGF and other signaling pathways in early induction and patterning.

FGF signaling has been implicated in germ layer formation and axial determination. An antibody specific for the activated form of mitogen-activated protein kinase (MAPK) was used to monitor FGF signaling in vivo during early Xenopus development. Activation of MAPK in young embryos is abolished by injection of a dominant negative FGF receptor (XFD) RNA, suggesting that MAPK is activated primarily by FGF in this context. A transition from cytoplasmic to nuclear localization of activated MAPK occurs in morula/blastula stage embryo animal and marginal zones coinciding with the proposed onset of mesodermal competence. Activated MAPK delineates the region of the dorsal marginal zone before blastopore formation and persists in this region during gastrulation, indicating an early role for FGF signaling in dorsal mesoderm. Activated MAPK was also found in posterior neural tissue from late gastrulation onward. Inhibition of FGF signaling does not block posterior neural gene expression (HoxB9) or activation of MAPK; however, inhibition of FGF signaling does cause a statistically significant decrease in the level of activated MAPK. These results point toward the involvement of other receptor tyrosine kinase signaling pathways in posterior neural patterning.

Active Transport, Cell Nucleus↗
PubMed2001

FGF-10 stimulates limb regeneration ability in Xenopus laevis.

By reciprocal transplantation experiments with regenerative and nonregenerative Xenopus limbs, we recently demonstrated that the regenerative capacity of a Xenopus limb depends on mesenchymal tissue and we suggested that fgf-10 is likely to be involved in this capacity (Yokoyama et al., 2000, Dev. Biol. 219, 18-29). However, the data obtained in that study are not conclusive evidence that FGF-10 is responsible for the regenerative capacity. We therefore investigated the role of FGF-10 in regenerative capacity by directly introducing FGF-10 protein into nonregenerative Xenopus limb stumps. Exogenously applied FGF-10 successfully stimulated the regenerative capacity, resulting in the reinduction of all gene expressions (including shh, msx-1, and fgf-10) that we examined and the regeneration of well-patterned limb structures. We report here for the first time that a certain molecule activates the regenerative capacity of Xenopus limb, and this finding suggests that FGF-10 could be a key molecule in possible regeneration of nonregenerative limbs in higher vertebrates.

Animals↗
PubMed1995

FGF-1 is a heparin-independent mitogen for rat hepatocytes.

We have found that in the primary culture of rat hepatocytes, the potent mitogenic activity of native FGF-1 is independent of heparin. The well-established characteristic of FGF-1 as a heparin-dependent mitogen is confirmed by human umbilical vein endothelial cells using the same preparation of FGF-1. Cross-linking experiments reveal that binding of FGF-1 to the hepatocyte cell surface receptors can be accomplished in the absence of exogenous heparin, in contrast to human endothelial cells for which it remains as a limiting factor. For both cell types, however, it is demonstrated that either endogenous or exogenous heparan sulfate/heparin moieties are essential for FGF-1 to establish receptor binding and mitogen action. Thus, the results suggest that hepatocytes harbor cell surface heparan sulfate moieties that are fully capable of utilizing FGF-1 in the environment. These results raise the possibility that FGF-1 is of differential potency for different cell types according to the nature and/or quantity of cell surface heparan sulfate moieties in vivo.

Animals↗
PubMed1996

IGF enhancement of FGF-induced fibre differentiation and DNA synthesis in lens explants.

The aim of this study was to carry but an analysis of the effects of insulin-like growth factors (IGFs) on responses induced by FGF in lens epithelial explants. Central explants from postnatal rats were cultured with concentrations of FGF-2 known to stimulate fibre differentiation or cell proliferation, with and without IGF-I or IGF-II at concentrations ranging from 0-1000 ng ml-1. Fibre-specific beta- and gamma-crystallin accumulation was determined by ELISA after 5-10 days culture and [3H]thymidine incorporation was assessed at 18-24 hr. Generally, both FGF and IGF were added on day 0. In the absence of FGF, IGF induced significant DNA synthesis, but negligible fibre differentiation. When included with FGF, however, IGF synergistically enhanced both DNA synthesis and the accumulation of fibre-specific crystallins. For beta-crystallin, it was shown that this enhancement reflected a substantial increase in the amount of crystallin in individual cells, not merely an increase in cell numbers. The potentiating effects of IGF-I and IGF-II were comparable. For the fibre differentiation response, it was shown that the cells remained responsive to the synergistic influence of IGF-1 for up to 4 days of culture. The dose response characteristics of the fibre differentiation response suggest that mediation occurs mainly through the IGF-I receptor. Because IGF, as well as FGF, is known to be present in the ocular media, IGF may have a role in modulating FGF-induced responses in the lens in vivo.

Animals↗
PubMed1998

Induction and maintenance of differentiation of rat lens epithelium by FGF-2, insulin and IGF-1.

The differentiation of rat lens epithelial cells to fibre cells can be mimicked using lens epithelial explants, which differentiate in vitro when exposed to fibroblast growth factor (FGF). A previous study demonstrated that FGF is required only for initiation of differentiation: once induced by FGF, differentiation can be maintained by insulin (as assessed by following the accumulation of fibre-cell specific crystallins). The aim of this investigation was to determine whether insulin-like growth factor 1 (IGF-1) can also maintain differentiation and to include a cellular analysis of explants undergoing insulin-or IGF-maintained differentiation in vitro. Measurement of the accumulation of alpha-, beta- and gamma-crystallins showed that IGF-1, like insulin, can replace FGF-2 in directing the pulses of alpha-, beta- and gamma-crystallin gene expression once differentiation is initiated by FGF-2. Cells in both the peripheral and the central region of the explants responded. Immunolocalization of alpha, beta- and gamma-crystallins in these explants showed that a 15 min pulse of FGF-2 triggered the differentiation of only a few cells, whereas a 12 hr pulse primed virtually all the cells for differentiation. This indicates that in explants, individual cells differ in the rate at which they can respond to FGF-2.

Animals↗
PubMed2000

Neural and angiogenic defects in eyes of transgenic mice expressing a dominant-negative FGF receptor in the pigmented cells.

Fibroblast growth factors (FGF) are multipotent cytokines with demonstrated mitogenic, neurotrophic and angiogenic properties. There is evidence that they have multiple functions during and after development of the vertebrate eye. Amongst these, the role of FGF receptor mediated signaling in the retinal pigmented epithelium (RPE) is not yet well understood. FGF-2 is produced in RPE cells and may play a role in photoreceptor development and/or survival in vivo. It may also stimulate growth of melanocytes and angiogenesis in the choroid. To address these questions, we have specifically disrupted FGF signaling by generating lines of transgenic mice expressing dominant-negative FGF receptor 1 (FGFR-1) in the pigmented cells. Histological analysis of the eyes were conducted on hemizygous and homozygous mice at different ages. In homozygotes, eye growth is strongly impaired during embryogenesis leading to massive eye degeneration seen in the early post-natal stages. In hemizygotes, the choroid is thinned and the finger-like junctions between RPE cells and photoreceptors are disrupted. Scanning electron microscopy of the choroid vasculature showed that choriocapillary density, diameter and branching are strongly affected. As mice age, they develop progressive retinal degeneration as evidenced by photoreceptor cell loss. Our results are in agreement with the hypothesis that FGF signaling in the RPE participates in photoreceptor survival in vivo. Our model provides evidence that FGF signaling is also involved in choroidal angiogenesis by a process that could relate to induction of terminal branching.

Animals↗
PubMed2004

Effects of FGF-2 on metaphyseal fracture repair in rabbit tibiae.

Fibroblast growth factor-2 (FGF-2) has been found to have stimulatory effects on fracture repair at diaphysis, while its effect on metaphyseal fracture repair, where spongiosal bone is dominant, has not been studied. This study was conducted to investigate the effect of FGF-2 on metaphyseal fracture healing in a rabbit proximal tibial metaphyseal model. The proximal tibial metaphysis of 6-month-old Japanese white rabbits was osteotomized bilaterally. Then 400 microg of FGF-2, mixed with gelatin hydrogel, and gelatin hydrogel alone (the control) were injected to each osteotomy site of the rabbit proximal tibiae, and the osteotomies were fixed with staples. One and 2 weeks after surgery, the osteoid area in the repairing spongiosal bone at the fracture site was significantly larger in the FGF-2 group than in the control group ( P < 0.05). On immunohistochemistry, proliferating-cell nuclear antigen-positive cells had a tendency to show greater numbers in the FGF-2 group. After 4 and 8 weeks, values for bone mineral density and the cancellous bone area in the healing region of the fracture site were significantly larger in the FGF-2 group ( P < 0.05). These data suggest that local application of FGF-2 may have an accelerating effect on the repair of metaphyseal fractures. Exogenous recombinant human rhFGF-2 may have potential clinical applications in metaphyseal fracture treatment.

Animals↗
PubMed2004

Expression of FGF-2 alters focal adhesion dynamics in migration-restricted MDA-MB-231 breast cancer cells.

Basic fibroblast growth factor (FGF-2) expression takes place during morphogenic differentiation of mammary ducts and is lost in breast cancer. Forced re-expression of FGF-2 in breast cancer cell lines induces a more differentiated phenotype and inhibits motility by unknown mechanisms. Here we demonstrate that MDA-MB-231 cells with encumbered motility due to forced re-expression of FGF-2 have activated focal complexes as determined by immunoprecipitation/western blotting and immunofluorescence staining with antibodies to FAK, p130Cas, paxillin, vinculin and phosphotyrosine. The activation of the focal adhesion complexes results in loss of stress fibers associated with malignant transformation of mammary epithelial cells and the formation of circumferentially-distributed actin bundles associated with non-transformed mammary epithelial cells. These effects require continuous FGF-2 expression, as the effects of exogenous recombinant FGF-2 are only small and transient. FGF-2 expression results in an increase in integrin alpha 3 expression and decreases in integrin beta 1 and beta 4 expression. These changes, however, induce only a small decrease in adhesion to uncoated and fibronectin-coated tissue culture dishes suggesting that the primary cause of impaired motility is due to intrinsic signaling. These data suggest that FGF-2-inhibits motility in breast cancer cells by stabilization of focal complexes and induction of a more differentiated phenotype with disruption of stress fiber formation and a characteristic cortical actin distribution.

Breast Neoplasms↗
PubMed2005

Immunolocalization of fibroblast growth factor-2 (FGF-2) in the developing root and supporting structures of the murine tooth.

Epithelio-mesenchymal interactions are active during the development of the root of the tooth and are regulated by a variety of growth factors, such as fibroblast growth factors. FGF-2, 3, 4, and 8 have all been shown to play a role in the development of the crown of the tooth, but less is known about the factors that govern root formation, particularly FGF-2. The aim of this study was thus to elucidate the spatial and temporal expression of FGF-2 in the root of the developing tooth, as this growth factor is believed to be a mediator of epithelio-mesenchymal interactions. Parasagittal sections of the maxillary and mandibular arches of post-natal mice were utilized and the roots of the molar teeth were studied. Immunocytochemistry utilizing an antibody to FGF-2 was performed on sections of teeth at various stages of development. Intense immunostaining for FGF-2 was observed in differentiating odontoblasts at the apical end of the tooth and in the furcation zone of the developing root at all the stages examined. FGF-2 localization was also observed in cementoblasts on post-natal days 16, 20 and 24. The pattern of localization of FGF-2 in the developing root suggests that this growth factor may participate in the signaling network associated with root development.

Ameloblasts↗
PubMed1989

Biological and chemical characterization of basic FGF-saporin mitotoxin.

Basic fibroblast growth factor (FGF) and saporin-6, a ribosome-inactivating protein, were chemically conjugated and characterized as a cytotoxin to cells expressing the basic FGF receptor. Structural and Western blot analysis of the conjugate showed that it contained saporin and basic FGF in equimolar amounts. The conjugate inhibited protein synthesis in a cell-free system and had potent cytotoxic activity (ID50 = 25pM) for cells expressing the basic FGF receptor. It is equipotent with basic FGF in radioreceptor assays and elutes from heparin Sepharose columns with 2M NaCl. The activity of the mitotoxin can be inhibited by competition with an excess of basic FGF but not nerve growth factor. The possibility that this mitotoxin can be used as an anti-angiogenic factor in paradigms that involve basic FGF is discussed.

Animals↗
PubMed1994

Fibroblast growth factor-2 (FGF-2) in the nucleus: translocation process and targets.

FGF-2 (basic fibroblast growth factor) was recently detected in the nucleus of a variety of cell types. The large isoforms contain a functional nuclear localization signal that allows their nuclear accumulation in producing cells, while a small amount of FGF-2 added exogenously to target cells is translocated to the nucleus in phase G1 of the cell cycle according to an unknown process. We report here using Chinese hamster ovary cell mutants bearing deficiency in heparan sulfate proteoglycans (HSPGs) synthesis that HSPGs are required for transport of exogenous FGF-2 to the nucleus. Furthermore a co-transport was suggested since an active complex containing FGF-2 and HSPGs was isolated from nuclei of treated cells. Several FGF-2 nuclear targets were described. In vivo as in vitro, it activates rDNA transcription and it binds to a specific DNA sequence that is present in the non-transcribed spacer of ribosomal genes. In vitro, FGF-2 has a strong affinity for histone H1 and it activates the protein kinase CKII. In the nucleus FGF-2 could regulate gene expression through modulation of chromatin structure.

Animals↗
PubMed1992

Purification of a heparin binding FGF receptor (HB-FGFR) from adult bovine brain membranes.

A new form of high affinity fibroblast growth factor receptor has been purified from adult bovine brain membranes. Purification was performed by chromatography on DEAE-Trisacryl and wheat germ agglutinin-agarose followed by FGF-2 affinity chromatography. Affinity labeling of purified fractions with 125I-FGF-2 showed after cross-linking a 170-kDa complex, suggesting the existence of a 150-kDa FGF receptor. No cross-reactivity with anti-FGF receptor 1 (FGFR-1 or flg) or with anti-receptor 2 (FGFR-2 or bek) antibodies could be detected with this partially purified receptor. Heparitinase treatment of the partially purified FGF receptor abolished the formation of the ligand receptor complex. The complex was restored in the presence of heparin in a dose dependent fashion, supporting the idea that heparin-like molecules are needed for proper binding. Further purification of the receptor was achieved by heparin-Sepharose affinity chromatography and yielded a purification of over 320,000-fold. The purified receptor fraction was radiolabeled and loaded on RPLC C4 column. Eluted fractions were analysed by SDS-PAGE. A major 150-kDa band was detected. These data show for the first time a new form of FGF receptor isolated from bovine brain membranes. This purified receptor displays affinity for heparin and was therefore named heparin binding FGF receptor (HB-FGFR). It remains unclear whether the receptor is a proteo-heparin sulfate or whether heparans are strongly associated and therefore are copurified. Large scale preparations are in progress for core protein structure studies.

Animals↗
PubMed1996

Basic fibroblast growth factor (FGF-2) affects development of acoustico-vestibular neurons in the chick embryo brain in vitro.

The effects of basic fibroblast growth factor (FGF-2) on presumptive auditory and vestibular neurons from the medulla were studied in primary cell cultures. The part of the rhombic lip that forms nucleus magnocellularis (homologue of the mammalian anteroventral cochlear nucleus) was explanted from white leghorn chicken embryos at Hamburger-Hamilton stage 28 (E5.5), the time when precursors of the magnocellularis bushy cells migrate and begin to differentiate in situ. In vitro the neuroblasts migrated onto 2-D substrates of purified collagen, differentiated, and expressed neuronal markers. One-half of the cultures were supplemented with human recombinant FGF-2 (10 ng/ml daily) for 5-7 days; the others, with fetal bovine serum. FGF-2 more than doubled the length of neurite outgrowth during the first 3 day treatment compared to serum, but the number of migrating neuroblasts was unaffected. Although neurites attained greater lengths in FGF-2, they usually degenerated after 4-5 days; in serum their growth continued for several weeks. Differentiation of neuronal structure, including axons and dendrites, began within 1-2 days in bFGF but required at least 5-7 days in serum. Histochemical observations in vitro and in situ with antibodies to FGF receptor demonstrated immunopositive patches on acoustico-vestibular neuroblasts at stage 28, when they are migrating and first forming their axons. The findings suggest that FGF-2 stimulates neurite outgrowth in the cochlear and vestibular nuclei. FGF-2 may accelerate cell death by overstimulating neuroblasts, but other factors are needed to sustain their further development.

Amino Acid Sequence↗
PubMed2004

Quantitative assessment of FGF regulation by cell surface heparan sulfates.

Heparin/heparan sulfate-like glycosaminoglycans (HSGAGs) modulate the activity of the fibroblast growth factor (FGF) family of proteins. Through interactions with both FGFs and FGF receptors (FGFRs), HSGAGs mediate FGF-FGFR binding and oligomerization leading to FGFR phosphorylation and initiation of intracellular signaling cascades. We describe a methodology to examine the impact of heparan sulfate fine structure and source on FGF-mediated signaling. Mitogenic assays using BaF3 cells transfected with specific FGFR isoforms allow for the quantification of FGF1 and FGF2 induced responses independent of conflicting influences. As such, this system enables a systematic investigation into the role of cell surface HSGAGs on FGF signaling. We demonstrate this approach using cell surface-derived HSGAGs and find that distinct HSGAGs elicit differential FGF response patterns through FGFR1c and FGFR3c. We conclude that this assay system can be used to probe the ability of distinct HSGAG species to regulate the activity of specific FGF-FGFR pairs.

Animals↗
PubMed2005

The fibroblast growth factor-binding protein FGF-BP.

Fibroblast growth factors (FGFs) are important regulators of cell migration, proliferation and differentiation, e.g., during embryogenesis and wound healing, and under several pathological conditions including tumor growth and tumor angiogenesis. Since heparin-binding FGFs are tightly bound to heparansulfate proteoglycans, and therefore, trapped in the extracellular matrix, their release through the action of an FGF-binding protein (FGF-BP) is one of the critical steps in FGF bioactivation. FGF-BP expression is highly tissue specific and strictly regulated through different promoter elements. Besides its role in embryogenesis and wound healing, FGF-BP is upregulated in several tumors and it is associated especially with early stages of tumor formation, where angiogenesis plays a critical role. Concomitantly, in several mouse tumor models, targeting of FGF-BP by ribozymes or RNA interference (RNAi) abolishes or reduces tumor growth and tumor angiogenesis. This indicates that FGF-BP can be rate-limiting for tumor growth and serves as an angiogenic switch molecule, and that it represents an increasingly promising target molecule in anti-tumor therapy.

Animals↗
PubMed2005

Fibroblast growth factors (FGF) in human myometrium and uterine leiomyomas in various stages of tumour growth.

We previously described that the growth of human uterine leiomyomas was associated with a significant remodelling of the extracellular matrix of these tumours. Significant weight-related increase of collagen and heparan sulphate contents was detected. The latter was known as a component, which bound some peptide growth factors, mainly FGFs, therefore it was decided to evaluate the amounts of acidic FGF (aFGF) and basic FGF (bFGF) in human myometrium and in leiomyomas of various weight and FGF-binding to tissue components. It was found that myometrium and uterine leiomyomas contain picogram amount of aFGF and nanogram amounts of bFGF. No free aFGF was found. Slight amounts of free bFGF were detected both in myometrium and in the tumours. The aFGF and most of bFGF existed in a form of complex with a high molecular component(s). These complexes were very stable and they did not dissociate in denaturation conditions. In comparison to myometrium the tumours contained several times more FGFs and their amounts distinctly increased during the tumour growth. The expression of FGF-receptor I (FGF RI) in the tumours was more distinct in comparison to myometrium. The extracts from myometrium did not bind exogenous 125I-bFGF. In contrast to that the tumours of different weights contained at least two high molecular weight FGF-binding components. One of them (150 kDa) corresponded to FGF-receptor. The other one (190-200 kDa) might be a heparan sulphate-proteoglycan. It seems that aFGF and bFGF play an important role in transformation of normal myometrium into leiomyoma and further growth of this tumour. The action of FGFs on tumour cells enhances biosynthesis of collagen and sulphated glycosaminoglycans, especially heparan sulphate which binds FGFs in the vicinity of cells and facilitates their interaction with membrane receptors. The effect of these processes may be further stimulation of tumour growth and remodelling of tumour extracellular matrix.

Animals↗