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PubMed1994

Potential mechanisms regulating the extracellular activities of basic fibroblast growth factor (FGF-2).

Basic fibroblast growth factor (FGF-2) is nearly ubiquitous in its distribution, leading numerous investigators to propose that there must exist highly specific mechanisms to regulate its bioavailability. Moreover, in each of the tissues where it can be localized, numerous cells are its potential target. The identification of these mechanisms could serve as an important step in developing novel strategies to inhibit FGF action. It could be possible to block such FGF-dependent activities as angiogenesis, tumor growth, reproduction, and selected diseases of cell proliferation. Over the course of the past several years, we have attempted to describe some of the processes that might regulate a target cell's ability to activate FGF-2 in its local milieu.

Animals↗
PubMed2005

PLAC1 expression increases during trophoblast differentiation: evidence for regulatory interactions with the fibroblast growth factor-7 (FGF-7) axis.

PLAC1 is a recently described, trophoblast-specific gene that localizes to a region of the X-chromosome important in placental development. Immunohistochemical analysis demonstrated that PLAC1 polypeptide localizes to the differentiated syncytiotrophoblast throughout gestation (8-41 weeks) as well as a small population of villous cytotrophoblasts. Consistent with these observations, quantitative RT-PCR demonstrated that PLAC1 mRNA increases more than 300-fold during cytotrophoblast differentiation in culture to form syncytiotrophoblasts. Agents known to be relevant to trophoblast differentiation were then tested for the ability to influence PLAC1 expression. Fibroblast growth factor-7 (FGF-7), also known as keratinocyte growth factor (KGF), stimulated PLAC1 mRNA expression approximately two-fold in the BeWo(b30) trophoblast cell line. FGF-7 stimulation was significantly inhibited by PD-98059 and wortmannin suggesting mediation via MAP kinase and PI-3 kinase-dependent signaling pathways. Interestingly, epidermal growth factor (EGF) treatment of trophoblasts had no effect on PLAC1 expression alone, but potentiated the effect of FGF-7, suggesting the presence of a regulatory interaction of the two growth factors. FGF-7 and its receptor, FGFR-2b, exhibited spatial overlap with PLAC1 suggesting these regulatory interactions are physiologically relevant during gestation. These data demonstrate PLAC1 expression is upregulated during trophoblast differentiation, localizing primarily to the differentiated syncytiotrophoblast. Furthermore PLAC1 expression is specifically regulated by peptide growth factors relevant to trophoblast differentiation.

Cell Differentiation↗
PubMed1995

Regulation of FGF-4 enhancer activity by transcription factor NF-Y.

Regulation of FGF-4 gene expression is controlled both by elements in the promoter and by an enhancer domain located in the untranslated region of the third exon. We have determined that transcription factor NF-Y binds to the FGF-4 promoter. We further show by mutational analysis that binding of NF-Y is essential for FGF-4 enhancer activity but has minimal effect on activity of the FGF-4 promoter alone.

Animals↗
PubMed1996

The basic fibroblast growth factor (FGF-2) antisense RNA (GFG) is translated into a MutT-related protein in vivo.

The basic fibroblast growth factor (FGF-2) gene is transcribed bidirectionally to yield multiple sense (coding) transcripts and a unique 1.5 kb antisense transcript which may regulate sense RNA stability. The antisense RNA also contains a long open reading frame that predicts a hypothetical protein with homology to the prokaryotic MutT antimutator proteins. However, translation of this protein has not previously been demonstrated. We employed antibodies against the conserved MutT-domain of the deduced human FGF-2 antisense protein (GFG) to demonstrate expression of an immunoreactive 24 kDa protein in liver extracts from Xenopus laevis, and two proteins of 28 and 35 kDa in rat liver. In rats, GFG protein expression detected by western blot was tissue-specific and correlated with the level of FGF-2 antisense mRNA expression. These findings demonstrate that, in addition to its possible RNA regulatory function, the FGF-2 antisense transcript is translated into a conserved MutT-related protein.

Amino Acid Sequence↗
PubMed2000

IL-6 promoter is modulated by the 24 kDa FGF-2 isoform fused to the hormone binding domain of the oestrogen receptor.

Fusion proteins consisting of the 24 kDa nuclear form of basic fibroblast growth factor (FGF-2), associated with the hormone binding domain of oestrogen receptor (HBD), convey oestrogen inducibility to FGF-2. When stable HBD-FGF-2 HeLa cell lines were transiently transfected with an interleukin 6 (IL-6) construct, the IL-6 promoter activity was downregulated by the addition of oestradiol. Moreover, in these cell lines, the function of the FGF-2 nuclear localisation sequence was abolished by its fusion to HBD, while addition of oestradiol restored the location of the chimera to the nucleus.

Binding Sites↗
PubMed1997

Localization of MAP kinase activity in early Xenopus embryos: implications for endogenous FGF signaling.

We have used a sensitive assay for MAP kinase activity to investigate the role of endogenous fibroblast growth factor (FGF)-activated MAP kinase in early Xenopus embryonic patterning. MAP kinase activity is low during cleavage stages and increases significantly during gastrulation. The temporal profile of this activity correlates well with the expression pattern of Xenopus eFGF. Spatially, MAP kinase activity is lowest in animal pole tissue and higher in vegetal pole cells and the marginal zone. Endogenous MAP kinase activity is FGF receptor-dependent, demonstrating that FGF signaling is active in all three germ layers of the early embryo. This activity is necessary for normal expression of Mix.1, a mesoendodermal marker, in the endoderm as well as in the mesoderm, indicating that MAP kinase plays a functional role in patterning of both of these germ layers. Spatial and temporal changes in MAP kinase activation during gastrulation also suggest a role for FGF signaling in this process. In addition, we find that embryonic wounding during dissection results in significant stimulation of this pathway, providing a possible explanation for earlier observations of effects of surgical manipulation on cell fate in early embryos.

Animals↗
PubMed2000

FGF signaling restricts the primary blood islands to ventral mesoderm.

According to the three-signal model of mesoderm patterning in Xenopus, all mesoderm, with the exception of the Spemann organizer, is originally specified as ventral type, such as lateral plate and primary blood islands. It is proposed that the blood islands become restricted to the ventralmost mesoderm because they are not exposed to the BMP-inhibiting activity of the Spemann organizer. We present evidence here that, contrary to predictions of this model, the blood islands remain ventrally restricted even in the absence of Spemann organizer signaling. We further observed that inhibition of FGF signaling with a dominant negative receptor resulted in the expansion of the blood island-forming territory with a concomitant loss of somite. The requirement for FGF signaling in specifying somite versus blood island territories was observed as early as midgastrulation. The nonoverlapping expression domains of Xnr-2 and Xbra in the gastrula marginal zone appear to mark presumptive blood island and somite, respectively. Inhibition of FGF signaling with dominant negative receptor leads to an expansion of Xnr-2 expression and to a corresponding reduction in Xbra expression. On the other hand, we found no evidence that manipulation of BMP signaling, either positively or negatively, altered the expression domains of Xnr-2 and Xbra. These results suggest that FGF signaling, rather than BMP-inhibiting activity, is essential for restriction of the ventral blood islands to ventral mesoderm.

Animals↗
PubMed2002

Inhibition of BMP activity by the FGF signal promotes posterior neural development in zebrafish.

The expression patterns of region-specific neuroectodermal genes and fate-map analyses in zebrafish gastrulae suggest that posterior neural development is initiated by nonaxial signals, distinct from organizer-derived secreted bone morphogenetic protein (BMP) antagonists. This notion is further supported by the misexpression of a constitutively active form of zebrafish BMP type IA receptor (CA-BRIA) in the zebrafish embryos. It effectively suppressed the anterior neural marker, otx2, but not the posterior marker, hoxb1b. Furthermore, we demonstrated that the cells in the presumptive posterior neural region lose their neural fate only when CA-BRIA and Xenopus dominant-negative fibroblast growth factor (FGF) receptors (XFD) are coexpressed. The indications are that FGF signaling is involved in the formation of the posterior neural region, counteracting the BMP signaling pathway within the target cells. We then examined the functions of Fgf3 in posterior neural development. Zebrafish fgf3 is expressed in the correct place (dorsolateral margin) and at the correct time (late blastula to early gastrula stages), the same point that the most precocious posterior neural marker, hoxb1b, is first activated. Unlike other members of the FGF family, Fgf3 had little mesoderm-inducing activity. When ectopically expressed, Fgf3 expands the neural region with suppression of anterior neural fate. However, this effect was mediated by Chordino (zebrafish Chordin), because Fgf3 induces chordino expression in the epiblast and Fgf3-induced neural expansion was substantially suppressed in dino mutants with mutated chordino genes. The results obtained in the present study reveal multiple actions of the FGF signal on neural development: it antagonizes BMP signaling within posterior neural cells, induces the expression of secreted BMP antagonists, and suppresses anterior neural fate.

Animals↗
PubMed2002

Ectodermal FGFs induce perinodular inhibition of limb chondrogenesis in vitro and in vivo via FGF receptor 2.

The formation of cartilage elements in the developing vertebrate limb, where they serve as primordia for the appendicular skeleton, is preceded by the appearance of discrete cellular condensations. Control of the size and spacing of these condensations is a key aspect of skeletal pattern formation. Limb bud cell cultures grown in the absence of ectoderm formed continuous sheet-like masses of cartilage. With the inclusion of ectoderm, these cultures produced one or more cartilage nodules surrounded by zones of noncartilaginous mesenchyme. Ectodermal fibroblast growth factors (FGF2 and FGF8), but not a mesodermal FGF (FGF7), substituted for ectoderm in inhibiting chondrogenic gene expression, with some combinations of the two ectodermal factors leading to well-spaced cartilage nodules of relatively uniform size. Treatment of cultures with SU5402, an inhibitor FGF receptor tyrosine kinase activity, rendered FGFs ineffective in inducing perinodular inhibition. Inhibition of production of FGF receptor 2 (FGFR2) by transfection of wing and leg cell cultures with antisense oligodeoxynucleotides blocked appearance of ectoderm- or FGF-induced zones of perinodular inhibition of chondrogenesis and, when introduced into the limb buds of developing embryos, led to shorter, thicker, and fused cartilage elements. Because FGFR2 is expressed mainly at sites of precartilage condensation during limb development in vivo and in vitro, these results suggest that activation of FGFR2 by FGFs during development elicits a lateral inhibitor of chondrogenesis that limits the expansion of developing skeletal elements.

Animals↗
PubMed1993

Cell motility, invasion, and malignancy induced by overexpression of K-FGF or bFGF.

We have tested the hypothesis that fibroblast growth factors contribute to cell locomotion and invasion, by investigating the properties of NIH-3T3 fibroblasts that secrete K-FGF following transfection with the K-fgf proto-oncogene and NIH-3T3 fibroblasts transfected with either the normal basic fibroblast growth factor (bFGF) coding sequence that lacks a known secretory signal sequence, or a chimeric bFGF sequence fused to an immunoglobulin signal sequence that targets the growth factor to the secretory pathway. The cell lines were tested for altered invasive characteristics on a physiologically relevant collagen substratum, and their motility rates were measured in cell locomotion assays using time-lapse video microscopy in the absence or presence of suramin, an inhibitor of growth factor-receptor interaction. The data were analyzed by comparing the motility rates of all K-fgf- and bFGF-transfected cell lines as a function of malignant potential. These studies show for the first time that K-fgf gene expression potently increases cell motility characteristics. Further, the bFGF transfectants generally exhibited increased rates of cell locomotion which were not dependent upon the presence of a signal sequence for secretion. These results support models of cell locomotion in which stimulation of this process can occur through both autocrine and intracrine pathways. In addition, a significant correlation was found to exist between cell locomotion and malignant potential, supporting the view that growth factor-induced motility, although not sufficient on its own to induce metastasis, is important in the promotion of tumor cell dissemination.

3T3 Cells↗
PubMed2000

Role for basic fibroblast growth factor (FGF-2) in tyrosine kinase (TrkB) expression in the early development and innervation of the auditory receptor: in vitro and in situ studies.

A previous study showed that basic fibroblast growth factor (FGF-2) promotes the effects of brain-derived neurotrophic factor (BDNF) on migration and neurite outgrowth from the cochleovestibular ganglion (CVG). This suggests that FGF-2 may up-regulate the receptor for BDNF. Thus we have examined TrkB expression during CVG formation and otic innervation in vitro and in the chicken embryo using immunohistochemistry. Following anatomical staging according to Hamburger-Hamilton, results were compared with mRNA expression in vitro using in situ hybridization. In the embryo at stage 16 (E2+) clusters of either lightly stained or immunonegative cells occurred within the otocyst and among those migrating to the CVG. By stage 22 (E3.5), immunostaining was concentrated in the CVG perikarya and invaded the processes growing into the otic epithelium but not into the rhombencephalon. Subsequently TrkB expression decreased in the perikarya and became localized in the leading processes of the fibers invading the epithelium and in the structures participating in synapse formation with the hair cells. In vitro there was moderate immunostaining and modest in situ hybridization for trkB in the neuroblasts migrating from the otocyst under control conditions. In contrast, neuroblasts previously exposed to FGF-2 exhibited accelerated migration and differentiation, with increased trkB mRNA expression. Morphological differentiation was associated with more intense immunostaining of processes than cell bodies. Evidently TrkB shifts its expression sequentially from sites engaged in migration, ganglion cell differentiation, axonal outgrowth, epithelial innervation, and synapse formation. FGF-2 may promote the role of BDNF in these developmental events by upregulating the TrkB receptor.

Animals↗
PubMed1994

Longitudinal changes in myocardial basic fibroblast growth factor (FGF-2) activity following coronary artery ligation in the dog.

Although fibroblast growth factor has been identified in normal and ischemic myocardium, temporal changes in mitogenic activity due to fibroblast growth factors in ischemic tissue have not been well established, nor has correlation been made with the known early increases in coronary collateral flow. This study sought to measure fibroblast growth factor activity in myocardium after coronary ligation. Accordingly the left anterior descending coronary artery of dogs was ligated and coronary collateral flow measured with radioactive microspheres. The heart was arrested after 2 h (four dogs), 1 week (four dogs), 2 weeks (three dogs), or 8 weeks (four dogs). Just before arrest collateral flow was again measured with radioactive microspheres, and the perfusion territory of the ligated vessel was demarcated with an intracoronary injection of Evans blue. The stained ischemic region was separated into central and peripheral portions. A transmural sample was removed from each portion for quantitation of tissue radioactivity and the rest was used for isolation of fibroblast growth factor and the measurement of mitogenic activity with vascular endothelial cells. To determine which fibroblast growth factor (FGF-1 or FGF-2) was being produced by the myocardium, aliquots of the isolated protein were first treated with specific antibodies to FGF-1 or FGF-2 before being assayed for mitogenicity. Coronary collateral flow did not change between 5 min and 2 h following coronary ligation, but was significantly increased at later time points. The ischemic/normal myocardial basic fibroblast growth factor mitogenic activity ratio in the peripheral ischemic tissue was increased after 2 h of ischemia (1.41 +/- 0.34), but the increase was not significant.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1995

A Ca2+/calmodulin kinase inhibitor, KN-62, inhibits neurite outgrowth stimulated by CAMs and FGF.

We have used monolayers of parental 3T3 fibroblasts and 3T3 cells expressing transfected cell adhesion molecules (CAMs, NCAM, N-cadherin, or L1) as a culture substrate for cerebellar neurons. Previous studies suggest that the transfected CAMs promote neurite outgrowth by activating a second messenger pathway within the responding neuron that involves influx of calcium into neurons as a consequence of activation of an FGF receptor. The same neurite outgrowth response can be induced by FGF or a number of agents that directly activate defined steps in the CAM signaling pathway. In the present study we show that the neurite outgrowth stimulated by the above three CAMs, FGF, arachidonic acid (AA), and K+ depolarization can be abolished by the Ca2+/calmodulin-dependent (CaM) kinase inhibitor, KN-62. We also demonstrate that neurite outgrowth over astrocytes, which represent a more physiologically relevant cellular substrate, can be substantially inhibited by a number of agents that block the CAM signaling pathway, including KN-62. However, neurite outgrowth induced by activation of protein kinase A is unaffected by inhibition of CaM kinase activity as is basal neurite outgrowth over 3T3 monolayers or a polylysine/laminin substrate. These results suggest that CaM kinase activity is specifically required downstream of calcium influx in the CAM and FGF signaling pathway leading to axonal growth.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗
PubMed2000

PDGF and FGF-2 signaling in oligodendrocyte progenitor cells: regulation of proliferation and differentiation by multiple intracellular signaling pathways.

In this paper we address the linking of platelet-derived growth factor (PDGF) and basic fibroblast growth factor (FGF-2) to intracellular signaling molecules in oligodendrocyte progenitors. It is demonstrated that both growth factors activate downstream targets similar to those shown for protein kinase C (PKC) activation. Yet, neither the arrest of terminal oligodendrocyte differentiation nor the proliferation induced by PDGF or FGF-2 can be antagonized by inhibition of PKC. Rather, p42/p44 mitogen-activated protein kinase (MAPK), p38 MAPK, and pp70 S6 kinase were found to be necessary for the mitogenic activity of PDGF and FGF-2. Paradoxically, these kinases were also necessary for the onset of oligodendrocyte differentiation in control cells. In addition, cAMP-dependent kinase A (PKA) activation inhibited the mitogenic response of oligodendrocyte progenitors to FGF-2. Taken together, the molecular mechanism that controls oligodendrocyte lineage progression is operated by at least two signal pathways, which interfere either with proliferation and/or differentiation of oligodendrocyte progenitors.

Animals↗
PubMed2002

A2B5+ and O4+ Cycling progenitors in the adult forebrain white matter respond differentially to PDGF-AA, FGF-2, and IGF-1.

Cycling glial progenitors reside within subcortical white matter of the mammalian adult forebrain. Either A2B5 or O4 expression defines two of the major classes of cycling progenitors. We examined the growth factor receptor profiles of these progenitor populations and their capability to proliferate and differentiate in response to PDGF-AA, FGF-2, and IGF-1. FGF-2 and IGF-1 enhance the acquisition of O1 by the O4+ progenitors, but have no significant effect on the acquisition of O4 and/or O1 by the A2B5+ progenitors. In contrast, PDGF-AA enhances the acquisition of O1 by the A2B5+ progenitors, while having no significant affect on the acquisition of O1 by the O4+ progenitors unless combined with FGF-2. In addition, PDGF-AA and FGF-2 promote the proliferation of A2B5+ progenitors, while having no mitogenic effect on the O4+ progenitors unless the two factors are combined with IGF-1. Interestingly, not all of the progenitors within the A2B5 or O4 populations express the same growth factor receptors nor respond similarly to growth factors. Thus, there are substantial differences between the two populations and heterogeneity within each of these populations may exist.

Animals↗
PubMed1999

Effects of NGF, b-FGF, and cerebrolysin on water maze performance and on motor activity of rats: short- and long-term study.

The effects of 14-day treatments with nerve growth factor (NGF), basic fibroblast growth factor (b-FGF), or the peptidergic drug Cerebrolysin on postlesion acquisition of a water maze task and on motor activity were evaluated. Rats were tested in the Morris water maze 14 days (early test) and 7 to 8 months (delayed test) after a bilateral lesion of the frontoparietal (sensorimotor) cortex. Only the rats treated with Cerebrolysin performed the water maze task at the level of the nonlesioned controls in the early test. No short-term effect of NGF (6.5 ng/14 days; 38 ng/ml) or b-FGF (17 ng/14 days; 100 ng/ml) treatment was found. The delayed test revealed that water maze performance was restored in rats treated with b-FGF in comparison with intact controls. The data showed that b-FGF can support or initiate processes in the CNS that lead to a delayed functional amelioration and/or compensation for a water maze performance deficit. NGF did not influence the acquisition impairment caused by a sensorimotor cortical lesion. Two-week administration of Cerebrolysin had a time-dependent influence: it attenuated the acquisition deficit and increased the motor activity of rats, both effects declined to the level of lesioned controls within 8 months.

Aging↗
PubMed1997

A proximo-distal gradient of FGF-like activity in the embryonic chick limb bud.

In a microassay for anchorage-independent growth in soft agar, NR6 cells form colonies in a dose-dependent manner in the presence of fibroblast growth factor (FGF). Using this assay system, the ability of thin sequential slices of embryonic chick limb bud to promote colony formation was investigated. A functional gradient of colony-promoting ability along the proximo-distal axis of the developing chick limb bud (stages 22-26) was observed. The highest number of colonies was observed in the presence of the most distal slices, and colony number decreased progressively at proximal levels. This gradient was specifically eliminated by the addition of anti-FGF antibody to the assay, indicating that it was caused by a functional gradient of an FGF-like molecule. Limbs of stages 21-26 were assayed: before this time limb buds are too small to slice in the proximo-distal axis in the required manner. The FGF-like gradient was observed at stages 22 to 26.

Animals↗
PubMed1998

Localization of fibroblast growth factor 2 (FGF-2) protein and the receptors FGFR 1-4 in normal human seminiferous epithelium.

Fibroblast growth factor 2 (FGF-2), which occurs in various isoforms both species and tissue specifically, regulates cell proliferation and differentiation via a dual receptor system consisting of heparan sulphate proteoglycans and receptor tyrosine kinases (FGFRs). This study demonstrates for the first time the distribution pattern of FGF-2 and the receptors FGFR 1-4 in the normal seminiferous epithelium of adult men. In western blot analyses, the polyclonal antibody, anti-FGF-2, shows two immunoreactive bands at 18 and 24 kDa. On paraffin sections, positive immunoreaction occurs within the cytoplasm of spermatogonia. The distribution pattern of the polyclonal anti-FGFR 1-4 antibodies is as follows: anti-FGFR-1 (one 68-kDa band) stains nuclei and cytoplasm of spermatogonia; anti-FGFR-3 (five bands at 68, 78, 105, 125 and 145 kDa) stains the nuclei of all germ cells except those of elongated spermatids; and anti-FGFR-4 (one 48-kDa band) stains the cytoplasm of primary pachytene spermatocytes. We were unable to demonstrate FGFR-2 immunoreactivity either in western blot analysis or on paraffin sections. This distribution pattern suggests that FGF-2 in spermatogonia is involved in the autocrine and paracrine regulation of the proliferation and differentiation of spermatogonia and spermatocytes via the receptors FGFR-1, FGFR-3 and FGFR-4.

Adult↗