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At least 1,063 records · Page 59Linked to original sources
PubMed2004

FGF-2 potently induces both proliferation and DSP expression in collagen type I gel cultures of adult incisor immature pulp cells.

We investigated the effects of both cytokines and extracellular matrices on the proliferation and differentiation of immature adult rat incisor dental pulp cells. These immature cells, which have a high-proliferative potency in vitro and do not express mRNAs for dentin non-collagenous proteins such as dentin sialoprotein (DSP), bone sialoprotein (BSP), and osteocalcin, exist in the root regions of adult rat incisors. Fibroblast growth factor-2 (FGF-2) stimulated the proliferation of these immature cells and the subsequent production of mineralized calcium was induced by beta-glycerophosphate treatment. Additionally, FGF-2 dramatically induced the expression of DSP and BSP mRNAs, but only in collagen type I gel cultures, whereas neither plate-coated collagen type I nor fibronectin, laminin or collagen type IV cultures could produce this effect and generate sufficient physiological levels of these transcripts. Although bone morphogenetic protein-4 could not induce the proliferation of immature dental pulp cells nor upregulate DSP mRNA expression, it had a synergistic effect upon DSP transcript levels in conjunction with FGF-2. These results suggest that both the presence of FGF-2 and the three-dimensional formation of immature dental pulp cells in collagen type I gel cultures are essential for both DSP expression and odontoblast differentiation. These observations provide valuable information concerning the study of the commitment and differentiation of odontoblast lineages, and also provide a basis for the rational design of cytokine and extracellular matrix based compounds for regenerative therapies in new dental treatments.

Animals↗
PubMed2005

Zebrafish Polycomb group gene ph2alpha is required for epiboly and tailbud formation acting downstream of FGF signaling.

We analyzed Polycomb group gene ph2alpha functionally in zebrafish embryos by a gene knock-down procedure using morpholino antisense oligos. Inhibition of ph2alpha message translation resulted in abnormal epibolic movements as well as a thick tailbud or incomplete covering of the yolk plug. At the 24hpf stage, morphants had short trunks and tails, phenotypes similar to those with disturbances in FGF signaling. Accordingly, we looked at the effects of ph2alpha expression upstream and downstream of the FGF pathway. Treatment with SU5402, an inhibitor of Fgfrs, or injection of dominant-negative Fgfr1 DNA markedly reduced ph2alpha expression in the tailbud. In addition, cells expressing mRNAs for no tail, spadetail, myoD, and papc, which are involved in FGF-related development of posterior mesoderm, were distributed abnormally. Collectively, the data argue that ph2alpha is required for epiboly and tailbud formation, acting downstream of the FGF signaling pathway.

Animals↗
PubMed2004

FGF-2 and S100beta immunoreactivities increase in reactive astrocytes, but not in microglia, in ascending dopamine pathways following a striatal 6-OHDA-induced partial lesion of the nigrostriatal system.

Partial lesions were induced in rat midbrain dopamine ascending pathways by intrastriatal injection of 6-hydroxydopamine (6-OHDA), and after two weeks changes were observed in the immunoreactivities of S100beta, a calcium-binding protein, and basic fibroblast growth factor (FGF-2), which is neurotrophic. Semiquantitative microdensitometric image analysis revealed increased intensities of FGF-2 and S100beta immunostaining in putative glial profiles of the ipsilateral neostriatum, pars compacta (SNc) and reticulata (SNr) of the substantia nigra and ventral tegmental area (VTA). Double immunofluorescence and immunoperoxidase procedures, using antibodies against glial fibrillary acidic protein and OX-42, showed that these increased immunoreactivities were restricted to reactive astrocytes; they were not observed in reactive microglia. These results indicate that reactive astrocytes may exert paracrine trophic actions through S100beta and FGF-2 in the midbrain dopamine ascending pathways after striatal 6-OHDA treatment. Interactions between S100beta and FGF-2 may be relevant to neuronal maintenance and repair following dopamine injury.

Animals↗
PubMed2003

Fgf signaling controls the number of phalanges and tip formation in developing digits.

Tetrapods have two pairs of limbs, each typically with five digits, each of which has a defined number of phalanges derived from an archetypal formula. Much progress has been made in understanding vertebrate limb initiation and the patterning processes that determine digit number in developing limb buds, but little is known about how phalange number is controlled. We and others previously showed that an additional phalange can be induced in a chick toe if sonic hedgehog protein is applied in between developing digit primordia. Here we show that formation of an additional phalange is associated with prolonged Fgf8 expression in the overlying apical ridge and that an Fgf Receptor inhibitor blocks its formation. The additional phalange is produced by elongation and segmentation of the penultimate phalange, suggesting that the digit tip forms when Fgf signaling ceases by a special mechanism, possibly involving Wnt signaling. Consistent with this, Fgfs inhibit tip formation whereas attenuation of Fgf signaling induces tip formation prematurely. We propose that duration of Fgf signaling from the ridge, responsible for elongation of digit primordia, coupled with a characteristic periodicity of joint formation, generates the appropriate number of phalanges in each digit. We also propose that the process that generates the digit tips is independent of that which generates more proximal phalanges. This has implications for understanding human limb congenital malformations and evolution of digit diversity.

Animals↗
PubMed2004

FGF8-like1 and FGF8-like2 encode putative ligands of the FGF receptor Htl and are required for mesoderm migration in the Drosophila gastrula.

BACKGROUND: Mesoderm migration in the Drosophila gastrula depends on the fibroblast growth factor (FGF) receptor Heartless (Htl). During gastrulation Htl is required for adhesive interactions of the mesoderm with the ectoderm and for the generation of protrusive activity of the mesoderm cells during migration. After gastrulation Htl is essential for the differentiation of dorsal mesodermal derivatives. It is not known how Htl is activated, because its ligand has not yet been identified. RESULTS: We performed a genome-wide genetic screen for early zygotic genes and identified seven genomic regions that are required for normal migration of the mesoderm cells during gastrulation. One of these genomic intervals produces upon its deletion a phenocopy of the htl cell migration phenotype. Here we present the genetic and molecular mapping of this genomic region. We identified two genes, FGF8-like1 and FGF8-like2, that encode novel FGF homologs and were only partially annotated in the Drosophila genome. We show that FGF8-like1 and FGF8-like2 are expressed in the neuroectoderm during gastrulation and present evidence that both act in concert to direct cell shape changes during mesodermal cell migration and are required for the activation of the Htl signaling cascade during gastrulation. CONCLUSIONS: We conclude that FGF8-like1 and FGF8-like2 encode two novel Drosophila FGF homologs, which are required for mesodermal cell migration during gastrulation. Our results suggest that FGF8-like1 and FGF8-like2 represent ligands of the Htl FGF receptor.

Amino Acid Sequence↗
PubMed2005

Posterior capsule opacification-like changes in rat lens explants cultured with TGFbeta and FGF: effects of cell coverage and regional differences.

Following cataract surgery, many patients suffer secondary loss of vision because of posterior capsule opacification (PCO), which arises when residual lens epithelial cells become aberrant and migrate into the light path. Transforming growth factor-beta (TGFbeta)-induced transdifferentiation of lens cells appears to play a key role in this process. Fibroblast growth factor (FGF) may also play a role by promoting the survival of TGFbeta-affected cells and influencing their subsequent behaviour. In the present study, the effects of two different TGFbeta and FGF treatment regimes were compared in rat lens epithelial explants with either low or high initial cell coverage. Explants treated with 50 pg ml(-1) TGFbeta2 and 20 ng ml(-1) FGF-2 sequentially (day 0, day 1) or simultaneously (day 0), then cultured for up to 30 days with FGF, were assessed by light microscopy and immunolocalisation of markers for transdifferentiation (alpha-smooth muscle actin (alphaSMA) and type I collagen) or lens epithelial phenotype (Pax6) and fibre differentiation (beta-crystallin). By day 4, most cells had lost Pax6 reactivity, alphaSMA reactivity was evident, and there were differences between growth factor treatment groups, low and high initial cell coverage explants, and peripheral and central regions of explants. On day 30 of culture, all explants were well populated with cells, irrespective of treatment and initial cell coverage, and exhibited diverse PCO-like morphological changes, with expression of transdifferentiation markers and beta-crystallin in virtually all cells. Such overall resilience to variations in conditions may contribute to the insidious nature of PCO, while factors related to observed early differences between groups may contribute to PCO pleiomorphism.

Actins↗
PubMed2003

Regulation of the FGF-4 gene by a complex distal enhancer that functions in part as an enhanceosome.

The exact mechanisms by which enhancers regulate transcription are currently under investigation. For some genes, activation is accomplished by an intricate array of enhancer cis-regulatory elements that direct the assembly of a gene-specific activation complex known as an "enhanceosome". Transcription of the fibroblast growth factor-4 (FGF-4) gene during early development is controlled by a powerful distal enhancer located 3 kb downstream of the transcription start site within the 3' untranslated region of the gene. Previous studies have shown that FGF-4 enhancer function is mediated by at least three critical positive cis-regulatory elements: an HMG, a POU, and a GT-box motif, which bind the transcription factors Sox-2, Oct-3, and Sp1/Sp3, respectively. In this study, we identify a second essential HMG motif within the FGF-4 enhancer that binds the transcription factor Sox-2. Moreover, we demonstrate that spatial alignment of the new HMG motif, relative the other enhancer cis-regulatory elements, is important. Based on findings presented in this report, and work published earlier, we propose that the previously identified core HMG and POU cis-regulatory elements of the FGF-4 enhancer are dependent on one another and function in an enhanceosome-like manner. In contrast, the HMG motif identified in this study is only partially dependent on the other enhancer cis-regulatory elements for its function.

Animals↗
PubMed2004

IGF-I and FGF-2 coordinately enhance cyclin D1 and cyclin E-cdk2 association and activity to promote G1 progression in oligodendrocyte progenitor cells.

A critical question in developmental neurobiology is how stem and progenitor cells interpret multiple signals to decide whether to proliferate or exit the cell cycle. Insulin-like growth factor (IGF)-I and fibroblast growth factor (FGF)-2 have known functions individually in development of neural stem cells as well as more restricted neuronal and glial progenitor cells. The goal of this study was to elucidate how IGF-I and FGF-2 coordinately regulate the cell cycle machinery in primary oligodendrocyte progenitors (OPs). IGF-I/FGF-2 synergistically increased the numbers of OP cells recruited into S phase. IGF-I enhanced FGF-2 induction of cyclin D1, activation of G(1) cyclin-cyclin-dependent kinase (cdk) complexes, and hyperphosphorylation of retinoblastoma protein (pRb). Moreover, IGF-I was required for G(2)/M progression. In contrast, FGF-2 decreased levels of the cdk inhibitor p27(Kip1) associated with cyclin E-cdk2. These studies provide a mechanistic basis for coordinate regulation of cell cycle progression in progenitor cells by multiple growth factors.

Animals↗
PubMed2005

Multiple signaling pathways regulate FGF-2-induced retinal ganglion cell neurite extension and growth cone guidance.

Growth cones use cues in their environment in order to grow in a directed fashion to their targets. In Xenopus laevis, fibroblast growth factors (FGFs) participate in retinal ganglion cell (RGC) axon guidance in vivo and in vitro. The main intracellular signaling cascades known to act downstream of the FGF receptor include the mitogen-activated protein kinase (MAPK), phospholipase Cgamma (PLCgamma) and phosphotidylinositol 3-kinase (PI3K) pathways. We used pharmacological inhibitors to identify the signaling cascade(s) responsible for FGF-2-stimulated RGC axon extension and chemorepulsion. The MAPK, PI3K and PLCgamma pathways were blocked by U0126, LY249002 and U73122, respectively. D609 was used to test a role for the phosphotidylcholine-PLC (PC-PLC) pathway. We determined that the MAPK and two PLC pathways are required for FGF-2 to stimulate RGC neurite extension in vitro, but the response of axons to FGF-2 applied asymmetrically to the growth cone depended only on the PLC pathways.

Animals↗
PubMed2004

FGF-2 enhances TGF-beta1-induced periosteal chondrogenesis.

The use of periosteum as a cell source for the in vitro engineering of grafts for articular cartilage repair requires the development of methods to obtain high viable cell numbers in the early stages of culture. In this study, we demonstrate that the addition of a mitogen, fibroblast growth factor-2 (FGF-2), during the early stage of the in vitro culture of periosteum in the presence of transforming growth factor-beta1 (TGF-beta1), significantly enhances cell proliferation, which results in increased neo-cartilage formation at later stages. Periosteal explants were cultured in vitro within alginate or agarose based gels in the presence of either FGF-2 for the first week, TGF-beta1 for the first 2 weeks, FGF-2 and TGF-beta1 for the first week and first 2 weeks respectively, or no added factors. Consistent with previous studies, periosteum derived neo-chondrogenesis occurred only in the presence of TGF-beta1. The neo-cartilage was found to contain cartilage specific proteoglycans and Type-II collagen as determined by safranin-O and immunohistochemical staining respectively. Further medium supplementation with FGF-2 stimulated early cell proliferation (>3 fold higher total DNA content per explant at day 10). This resulted in a marked increase in the size of the cultured explants and in the total area of the explant staining positive for safranin-O (from around 50% to 85%, (p<0.05)) after 6 weeks culture. The ability to generate significant quantities of neo-cartilage within a biocompatible and biodegradable matrix such as alginate, which lacks the immunogenicity of agarose, could open new pathways to utilizing such constructs in articular cartilage tissue engineering applications.

Alginates↗
PubMed2004

Evolution of the Fgf and Fgfr gene families.

Fibroblast growth factors (Fgfs) and Fgf receptors (Fgfrs) comprise a signaling system that is conserved throughout metazoan evolution. Twenty-two Fgfs and four Fgfrs have been identified in humans and mice. During evolution, the Fgf family appears to have expanded in two phases. In the first phase, during early metazoan evolution, Fgfs expanded from two or three to six genes by gene duplication. In the second phase, during the evolution of early vertebrates, the Fgf family expanded by two large-scale gen(om)e duplications. By contrast, the Fgfr family has expanded only in the second phase. However, the acquisition of alternative splicing by Fgfrs has increased their functional diversity. The mechanisms that regulate alternative splicing have been conserved since the divergences of echinoderms and vertebrates. The expansion of the Fgf and Fgfr gene families has enabled this signaling system to acquire functional diversity and, therefore, an almost ubiquitous involvement in developmental and physiological processes.

Animals↗
PubMed2006

Vhnf1 acts downstream of Bmp, Fgf, and RA signals to regulate endocrine beta cell development in zebrafish.

Bmp, Fgf, and retinoic acid (RA) signals have been implicated as regulators of pancreas development. However, the integration of these signaling pathways in vivo is not fully understood. Variant hnf1 (Vhnf1) is a transcription factor involved in pancreas, liver, and kidney development and its mutation in zebrafish causes underdeveloped pancreas and liver. We investigated the signaling pathways that regulate vhnf1 expression during pancreas development. First, we showed that Bmp activity is required for vhnf1 expression in the endoderm. In chordin (a Bmp antagonist) morpholino (MO)-injected embryos, vhnf1 expression in endoderm and in endocrine beta cells is expanded. On the other hand, in alk8 (a type I TGFbeta receptor) MO-injected embryos, vhnf1 expression in the endoderm is significantly reduced. Second, we showed that Fgf signaling participates in regulation of pancreas development through the vhnf1 pathway. Third, we demonstrated that RA fails to rescue reduction of insulin expression in vhnf1 mutants, whereas overexpression of vhnf1 restores insulin expression that is repressed by treatment with a RA receptor inhibitor. And finally, we revealed that both Bmp and Fgf signals act genetically upstream of RA in directing pancreas development. Taken together, our data establish that vhnf1 acts downstream of the signaling pathways of RA, Bmp, and Fgf to regulate pancreas development in zebrafish.

Animals↗
PubMed1988

Basic fibroblast growth factor (FGF) promotes cartilage repair in vivo.

Although it has been clearly established that basic fibroblast growth factor (FGF) is a potent mitogen for chondrocytes in vitro, there is little evidence that it can stimulate this cell type in vivo. In an effort to address this problem, we examined the effect of an intraarticular administration of basic FGF. Alzet osmotic pumps delivering the mitogen to the site of injury promotes the healing of intra-chondrial lesions by stimulating chondrocyte proliferation and the formation of extracellular matrix. The observation that chronic infusions of basic FGF can elicit a repair response at the site of injury suggests that this growth factor may have therapeutic applications that extend beyond its capacity to induce neovascularization. The results also suggest that one of the ways that the perichondrium mediates cartilage repair may be by the local production of FGF-like mitogens.

Animals↗
PubMed1998

Fibroblast growth factor (FGF)-9 immunoreactivity in senile plaques.

We examined fibroblast growth factor (FGF)-9 immunoreactivity in human hippocampal sections of Alzheimer's disease (AD). FGF-9 immunoreactivity was observed in dystrophic neurites of senile plaques in AD and control cases, in addition to the hippocampal and cortical neurons. The amyloid core and neurofibrillary tangles lacked immunoreactivity. FGF-9 immunoreactive astrocytes were conspicuous in AD brains. FGF-9 may be involved in the neuropathology of AD.

Alzheimer Disease↗
PubMed2002

Angiogenesis-independent cardioprotection in FGF-1 transgenic mice.

OBJECTIVE: This study was performed to evaluate the cardioprotective role of acidic fibroblast growth factor-1 (FGF-1) in transgenic mice with cardiac-specific overexpression of human FGF-1. METHODS: Mice were subjected to coronary artery occlusion for 15-75 min with a continuously recorded 3-lead electrocardiogram (ECG). Infarct size was measured and ERK-1 and -2 activity was assessed by Western blot analysis. Creatine kinase and lactate dehydrogenase activity as marker for cell viability were measured in isolated ventricular myocytes subjected to simulated ischemia. RESULTS: Infarct development was markedly delayed in transgenics with first signs of myocardial infarction visible at 45 min after coronary artery occlusion compared to 15 min in wildtype. Maximal infarct size (60% of risk area) did not differ, but transgenics reached maximal infarction after 75 min compared to 45 min in wildtype animals. ECG revealed delayed Q-wave development and delayed ST-segment elevation in transgenics. Creatine kinase and lactate dehydrogenase release was significantly attenuated from isolated transgenic myocytes at 4 and 8 h after simulated ischemia. The delay in infarct development is partially due to a constitutive higher expression of the extracellular signal-regulated kinases ERK-1 and -2 in the myocardium of transgenics. Additionally, injection of the ERK-1/2 inhibitor UO126 decreased the cardioprotective effect of FGF-1. CONCLUSION: Cardiac specific overexpression of FGF-1 provides cardioprotection at the level of the cardiac myocyte, independent from angiogenesis, and at least partially mediated via activation of the mitogen activated protein kinase (MAP) ERK-1 and -2.

Analysis of Variance↗
PubMed2003

Drosophila perlecan modulates FGF and hedgehog signals to activate neural stem cell division.

Mutations in the Drosophila trol gene cause cell cycle arrest of neuroblasts in the larval brain. Here, we show that trol encodes the Drosophila homolog of Perlecan and regulates neuroblast division by modulating both FGF and Hh signaling. Addition of human FGF-2 to trol mutant brains in culture rescues the trol proliferation phenotype, while addition of a MAPK inhibitor causes cell cycle arrest of the regulated neuroblasts in wildtype brains. Like FGF, Hh activates stem cell division in the larval brain in a Trol-dependent fashion. Coimmunoprecipitation studies are consistent with interactions between Trol and Hh and between mammalian Perlecan and Shh that are not competed with heparin sulfate. Finally, analyses of mutations in trol, hh, and ttv suggest that Trol affects Hh movement. These results indicate that Trol can mediate signaling through both of the FGF and Hedgehog pathways to control the onset of stem cell proliferation in the developing nervous system.

Alleles↗
PubMed2003

An Ets transcription factor, HrEts, is target of FGF signaling and involved in induction of notochord, mesenchyme, and brain in ascidian embryos.

In ascidian embryos, a fibroblast growth factor (FGF) signal induces notochord, mesenchyme, and brain formation. Although a conserved Ras/MAPK pathway is known to be involved in this signaling, the target transcription factor of this signaling cascade has remained unknown. We have isolated HrEts, an ascidian homolog of vertebrate Ets1 and Ets2, to elucidate the transcription factor involved in the FGF signaling pathway in embryos of the ascidian Halocynthia roretzi. Maternal mRNA of HrEts was detected throughout the entire egg cytoplasm and early embryos. Its zygotic expression started in several tissues, including the notochord and neural plate. Overexpression of HrEts mRNA did not affect the general organization of the tadpoles, but resulted in formation of excess sensory pigment cells. In contrast, suppression of HrEts function by morpholino antisense oligonucleotide resulted in severe abnormalities, similar to those of embryos in which the FGF signaling pathway was inhibited. Notochord-specific Brachyury expression at cleavage stage and notochord differentiation at the tailbud stage were abrogated. Formation of mesenchyme cells was also suppressed, and the mesenchyme precursors assumed muscle fate. In addition, expression of Otx in brain-lineage blastomeres was specifically suppressed. These results suggest that an Ets transcription factor, HrEts, is involved in signal transduction of FGF commonly in notochord, mesenchyme, and brain induction in ascidian embryos.

Amino Acid Sequence↗
PubMed2003

Smad mediates BMP-2-induced upregulation of FGF-evoked PC12 cell differentiation.

We previously reported that bone morphogenetic protein (BMP)-2 augments fibroblast growth factor (FGF)-induced neuronal differentiation of PC12 cells by selectively upregulating FGF receptor (FGFR)-1 expression. Here we describe the underlying mechanism. BMP-2 activated Smad proteins in PC12 cells. Overexpression of Smad7 or Smad1, inhibitory and receptor-regulated isoforms, respectively, suppressed or enhanced BMP-2-induced upregulation of FGFR-1 expression. Smad 7 also inhibited the FGF-induced PC12 differentiation. Our findings indicate that activation of a Smad signaling pathway is required for upregulation of FGFR-1 expression by BMP-2 and for the synergistic induction of PC12 differentiation by BMP-2 and FGF.

Animals↗