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At least 901 records · Page 50Linked to original sources
PubMed2005

Differentially promoted peripheral nerve regeneration by grafted Schwann cells over-expressing different FGF-2 isoforms.

Artificial nerve grafts are needed to reconstruct massive defects in the peripheral nervous system when autologous nerve grafts are not available in sufficient amounts. Nerve grafts containing Schwann cells display a suitable substrate for long-distance regeneration. We present here a comprehensive analysis of the in vivo effects of different isoforms of fibroblast growth factor-2 (FGF-2) on peripheral nerve regeneration across long gaps. FGF-2 isoforms were provided by grafted, genetically modified Schwann cells over-expressing 18-kDa-FGF-2 and 21-/23-kDa-FGF-2, respectively. Functional tests evaluated motor and sensory recovery. Additionally, morphometrical analyses of regenerated nerves were performed 3 and 6 months after grafting. Distinct regeneration promoting effects of the different FGF-2 isoforms were found. 18-kDa-FGF-2 mediated inhibitory effects on the grade of myelination of regenerating axons, whereas 21-/23-kDa-FGF-2 mediated early recovery of sensory functions and stimulation of long-distance myelination of regenerating axons. The results contribute to the development of new therapeutic strategies in peripheral nerve repair.

Animals↗
PubMed2006

Transgenic expression of human FGF-1 protects against hypoxic-ischemic injury in perinatal brain by intervening at caspase-XIAP signaling cascades.

Perinatal hypoxia-ischemia (HI) is a major cause of neurological disability and mortality in infant and children. In the present study, we explored the neuroprotective efficacy of FGF-1 in a rat model of perinatal HI. Carotid ligation combined with hypoxia caused marked infarctions in the ipsilateral cerebral hemisphere with significant loss of ipsilateral striatal, cortical and hippocampal volumes. Morphological analyses revealed both apoptotic and necrotic form of neuronal death determined by Nissl histology, dark-field microscopy and TUNEL staining. HI induced a marked increase in activated caspase-9, caspase-3 and PARP cleavage at 12 h to 7 days after HI in brain areas displaying TUNEL (+) cells. In addition, expression of the anti-apoptotic protein X-linked inhibitor of apoptosis (XIAP) was decreased under similar conditions of HI. Expression of human FGF-1 in brain significantly reduced the extent of both apoptotic and necrotic injury caused by HI. FGF-1 attenuated the HI-induced increase in activated caspase-3, caspase-9 and cleaved PARP protein levels and markedly blocked the HI-induced decrease in XIAP expression under the conditions at which FGF-1 showed significant neuroprotection. These findings demonstrate that FGF-1 prevents the onset of both apoptotic and necrotic death in neurons otherwise "destined to die" following hypoxic-ischemic injury by intervening at the level of caspase-signaling cascades and by restoring prosurvival protein XIAP expression in central neurons.

Animals↗
PubMed2005

Effects of acupuncture on the expression of glial cell line-derived neurotrophic factor (GDNF) and basic fibroblast growth factor (FGF-2/bFGF) in the left sixth lumbar dorsal root ganglion following removal of adjacent dorsal root ganglia.

This investigation studied the temporal changes in the expression of GDNF and FGF-2 in the left sixth lumbar (L6) dorsal root ganglion (DRG) after acupuncture in adult cats subjected to unilateral removal of adjacent DRG. The cats were divided into three groups. Group I were normal control animals. Group II cats were subjected to removal of DRG associated with the left L1-L5 and L7-S2 spinal nerves, sparing the L6 DRG. Group III cats received similar treatment as Group II ones, but in addition were subjected to acupuncture on the left side at acupuncture points (xuewei) the day after the operation. Both Groups II and III animals were perfused under anesthesia at 7 and 14 days post-operation (dpo) and their left DRG were processed for the immunohistochemical demonstration of GDNF and FGF-2. Following removal of adjacent DRG, the average number of all GDNF stained neurons in L6 DRG was decreased at 7 dpo and more so at 14 dpo. Acupuncture reversed this trend, as demonstrated in the increased average number of immunopositive small-to-medium sized neurons. FGF-2 expression was also less marked at 7 dpo but returned to normal at 14 dpo. Acupuncture significantly increased the average number of FGF-2 positive neurons compared with that in operated animals. This increase was observed in both large and small-to-medium sized neurons. In conclusion, our results demonstrated that the average number of GDNF and FGF-2 neurons in L6 DRG was decreased after unilateral removal of adjacent DRG but acupuncture could reverse some of the changes.

Acupuncture Therapy↗
PubMed2004

Acceleration of surgical angiogenesis in necrotic bone with a single injection of fibroblast growth factor-2 (FGF-2).

The aim of this study was to accelerate angiogenesis in necrotic bone by combining vascular bundle implantation and fibroblast growth factor-2 (FGF-2) administration. Twenty-four Japanese white rabbits were evaluated in this study. A portion of a rabbit iliac crest bone was removed as a free bone graft and frozen in liquid nitrogen to ensure complete cellular necrosis. A narrow hole was created in the bone and the graft was placed in the proximal thigh. In group 1, FGF-2 was injected into the hole at a single dose of 100 microg, and the saphenous artery and its venae comitantes were passed through the hole of the bone. In group 2, injection of saline into the hole and the vascular bundle implantation was used as a control. Neovascularization around the vessel was evaluated at weeks 1 and 2 after surgery. Neovascularization was observed along the implanted vascular bundle in both groups. At both 1 and 2 weeks after surgery, the vessel density of group 1 was significantly higher than that of group 2. The average length of newly formed vessels of group 1 was also significantly longer than that of group 2 at both 1 and 2 weeks after surgery. Both the vessel density and length were greater in week 2 animals than week 1. A local single injection of FGF-2 improved surgical angiogenesis in necrotic bone in this study. As FGF-2 is recognized as a potent mitogen for a variety of mesenchymal cells, the combination of vascular bundle implantation and FGF-2 administration may contribute to the treatment of ischemic osteonecrosis.

Animals↗
PubMed2003

Fgf signalling is required for formation of cartilage in the head.

Characterisation of human craniofacial syndromes and studies in transgenic mice have demonstrated the requirement for Fgf signalling during morphogenesis of membrane bone of the cranium. Here, we report that Fgf activity is also required for development of the oro-pharyngeal skeleton, which develops first as cartilage with some elements subsequently becoming ossified. We show that inhibition of FGF receptor activity in the zebrafish embryo following neural crest emigration from the neural tube results in complete absence of neurocranial and pharyngeal cartilages. Moreover, this Fgf signal is required during a 6-h period soon after initiation of neural crest migration. The spatial and temporal expression of Fgf3 and Fgf8 in pharyngeal endoderm and ventral forebrain and its correlation with patterns of Fgf signalling activity in migrating neural crest makes them candidate regulators of cartilage development. Inhibition of Fgf3 results in the complete absence of cartilage elements that normally form in the third, fourth, fifth, and sixth pharyngeal arches, while those of the first, second, and seventh arches are largely unaffected. Inhibition of Fgf8 alone has variable, but mild, effects. However, inhibition of both Fgf3 and Fgf8 together causes a complete absence of pharyngeal cartilages and the near-complete loss of the neurocranial cartilage. These data implicate Fgf3 and Fgf8 as key regulators of cartilage formation in the vertebrate head.

Animals↗
PubMed2004

FGF signaling is required for determination of otic neuroblasts in the chick embryo.

The interplay between intrinsic and extrinsic factors is essential for the transit into different cell states during development. We have analyzed the expression and function of FGF10 and FGF-signaling during the early stages of the development of otic neurons. FGF10 is expressed in a highly restricted domain overlapping the presumptive neurogenic region of the chick otic placode. A detailed study of the expression pattern of FGF10, proneural, and neurogenic genes revealed the following temporal sequence for the onset of gene expression: FGF10>Ngn1/Delta1/Hes5>NeuroD/NeuroM. FGF10 and FGF receptor inhibition cause opposed effects on cell determination and cell proliferation. Ectopic expression of FGF10 in vivo promotes an increase in NeuroD and NeuroM expression. BrdU incorporation experiments showed that the increase in NeuroD-expressing cells is not due to an increase in cell proliferation. Inhibition of FGF receptor signaling in otic explants causes a severe reduction in Neurogenin1, NeuroD, Delta1, and Hes5 expression with no change in non-neural genes like Lmx1. However, it does not interfere with NeuroD expression within the CVG or with neuroblast delamination. The loss of proneural gene expression caused by FGF inhibition is not caused by decreased cell proliferation or by increased cell death. We suggest that FGF signaling in the otic epithelium is required for neuronal precursors to withdraw from cell division and irreversibly commit to neuronal fate.

Animals↗
PubMed2004

Runx2 mediates FGF signaling from epithelium to mesenchyme during tooth morphogenesis.

Runx2 (Cbfa1) is a runt domain transcription factor that is essential for bone development and tooth morphogenesis. Teeth form as ectodermal appendages and their development is regulated by interactions between the epithelium and mesenchyme. We have shown previously that Runx2 is expressed in the dental mesenchyme and regulated by FGF signals from the epithelium, and that tooth development arrests at late bud stage in Runx2 knockout mice [Development 126 (1999) 2911]. In the present study, we have continued to clarify the role of Runx2 in tooth development and searched for downstream targets of Runx2 by extensive in situ hybridization analysis. The expression of Fgf3 was downregulated in the mesenchyme of Runx2 mutant teeth. FGF-soaked beads failed to induce Fgf3 expression in Runx2 mutant dental mesenchyme whereas in wild-type mesenchyme they induced Fgf3 in all explants indicating a requirement of Runx2 for transduction of FGF signals. Fgf3 was absent also in cultured Runx2-/- calvarial cells and it was induced by overexpression of Runx2. Furthermore, Runx2 was downregulated in Msx1 mutant tooth germs, indicating that it functions in the dental mesenchyme between Msx1 and Fgf3. Shh expression was absent from the epithelial enamel knot in lower molars of Runx2 mutant and reduced in upper molars. However, other enamel knot marker genes were expressed normally in mutant upper molars, while reduced or missing in lower molars. These differences between mutant upper and lower molars may be explained by the substitution of Runx2 function by Runx3, another member of the runt gene family that was upregulated in upper but not lower molars of Runx2 mutants. Shh expression in mutant enamel knots was not rescued by FGFs in vitro, indicating that in addition to Fgf3, Runx2 regulates other mesenchymal genes required for early tooth morphogenesis. Also, exogenous FGF and SHH did not rescue the morphogenesis of Runx2 mutant molars. We conclude that Runx2 mediates the functions of epithelial FGF signals regulating Fgf3 expression in the dental mesenchyme and that Fgf3 may be a direct target gene of Runx2.

Animals↗
PubMed2005

FGF signal regulates gastrulation cell movements and morphology through its target NRH.

We used cDNA microarray analysis to screen for FGF target genes in Xenopus embryos treated with the FGFR1 inhibitor SU5402, and identified neurotrophin receptor homolog (NRH) as an FGF target. Causing gain of NRH function by NRH mRNA or loss of NRH function using a Morpholino antisense-oligonucleotide (Mo) led to gastrulation defects without affecting mesoderm differentiation. Depletion of NRH by the Mo perturbed the polarization of cells in the dorsal marginal zone (DMZ), thereby inhibiting the intercalation of the cells during convergent extension as well as the filopodia formation on DMZ cells. Deletion analysis showed that the carboxyl-terminal region of NRH, which includes the "death domain," was necessary and sufficient to rescue gastrulation defects and to induce the protrusive cell morphology. Furthermore, we found that the FGF signal was both capable of inducing filopodia in animal cap cells, where they do not normally form, and necessary for filopodia formation in DMZ cells. Finally, we demonstrated that FGF required NRH function to induce normal DMZ cell morphology. This study is the first to identify an in vivo role for FGF in the regulation of cell morphology, and we have linked this function to the control of gastrulation cell movements via NRH.

Animals↗
PubMed2006

Overlapping expression of FoxA and Zic confers responsiveness to FGF signaling to specify notochord in ascidian embryos.

Differences in cell responsiveness to an inductive signal contribute to the emergence of a variety of tissue types during animal development. In ascidian embryos, the Fibroblast Growth Factor (FGF) signal secreted from endoderm cells induces several different tissue types, such as notochord, mesenchyme and brain, at different positions in the embryo at the 32-cell stage. We show here in Halocynthia roretzi that FoxA and Zic are required for notochord formation in cells that receive the FGF signal. We also show that these transcription factors, only when both are supplied, are able to induce ectopic expression of the brachyury gene, a notochord-specific marker, in cells of all the three germ layers in an FGF-dependent manner. These results suggest that FoxA and Zic confer notochord-specific responsiveness to FGF signaling. Further analyses including knockdown and over-expression experiments showed that combinatorial inputs from maternally supplied and zigotically activated factors lead to overlapping expression of FoxA and Zic in the presumptive notochord cells, which eventually activate the expression of the brachyury gene in cooperation with FGF signaling. Our data illustrate how a complex gene network specifies the notochord at its specific position within the embryo.

Animals↗
PubMed2006

FGF signal transduction and the regulation of Cdx gene expression.

Cdx homeodomain transcription factors play important roles in the development of the vertebrate body axis and gut epithelium. Signaling involving FGF, wnt and retinoic acid ligands has been implicated in the regulation of individual Cdx genes. In this study we examine the requirement for FGF-dependent signal transduction pathways in the regulation of Cdx gene expression. In the amphibian Xenopus laevis the earliest expression of Cdx1, Cdx2 and Cdx4 is within the developing mesoderm. We show that a functional FGF signaling pathway is required for the normal expression of all three amphibian Cdx genes during gastrula stages. We show that FGF stimulation activates signaling through both the MAP kinase pathway and the PI-3 kinase pathway in Xenopus tissue explants. However, our analysis of these pathways in gastrula stage embryos indicates that the MAP kinase pathway is required for Cdx gene expression, whereas the PI-3 kinase pathway is not. We show that FGF and wnt signaling can interact in the regulation of Cdx genes and during gastrula stages the normal expression of the Cdx genes requires the activity of both pathways. Furthermore, we show that wnt mediated Cdx regulation is independent of the MAP kinase pathway.

Animals↗
PubMed2006

Fgf signaling negatively regulates Nodal-dependent endoderm induction in zebrafish.

In zebrafish development, Nodal signaling is critical for the induction of endoderm and mesoderm. Three transcription factors downstream of Nodal, Bonnie and Clyde (Bon), Faust (Fau)/Gata5 and Casanova (Cas), are required for endoderm induction. However, it is not yet fully understood how the Nodal signaling pathway regulates the decision process of endoderm and mesoderm induction. In this study, we focused on Fgf signaling, downstream of Nodal signaling, during endoderm induction. We found that activation of Fgf signaling decreases the number of cas-expressing endodermal cells. Conversely, inhibition of this signaling increases the number of endodermal cells without affecting the expression of Nodal, Nodal antagonists, bon or fau/gata5. Inhibition of Fgf signaling in endoderm mutants suggests that this signaling negatively regulates cas expression by a pathway parallel to Bon and Fau/Gata5 in the molecular cascade leading to endoderm. Furthermore, activation of Fgf signaling can overcome Cas-mediated abrogation of mesodermal gene expression. Altogether, these results suggest that Fgf signaling negatively regulates endoderm induction, possibly through repression of cas expression and down-regulation of Cas function.

Animals↗
PubMed1999

Reversible thermal denaturation of human FGF-1 induced by low concentrations of guanidine hydrochloride.

Human acidic fibroblast growth factor (FGF-1) is a powerful mitogen and angiogenic factor with an apparent melting temperature (Tm) in the physiological range. FGF-1 is an example of a protein that is regulated, in part, by stability-based mechanisms. For example, the low Tm of FGF-1 has been postulated to play an important role in the unusual endoplasmic reticulum-independent secretion of this growth factor. Despite the close relationship between function and stability, accurate thermodynamic parameters of unfolding for FGF-1 have been unavailable, presumably due to effects of irreversible thermal denaturation. Here we report the determination of thermodynamic parameters of unfolding (DeltaH, DeltaG, and DeltaCp) for FGF-1 using differential scanning calorimetry (DSC). The thermal denaturation is demonstrated to be two-state and reversible upon the addition of low concentrations of added guanidine hydrochloride (GuHCl). DeltaG values from the DSC studies are in excellent agreement with values from isothermal GuHCl denaturation monitored by fluorescence and circular dichroism (CD) spectroscopy. Furthermore, the results indicate that irreversible denaturation is closely associated with the formation of an unfolding intermediate. GuHCl appears to promote reversible two-state denaturation by initially preventing aggregation of this unfolding intermediate, and at subsequently higher concentrations, by preventing formation of the intermediate.

Calorimetry, Differential Scanning↗
PubMed1997

Physical exercise induces FGF-2 and its mRNA in the hippocampus.

Clinical and experimental evidence indicate that physical activity has a positive impact on brain function; however, the molecular bases for how exercise affects the structure and function of the brain are largely unknown. We have investigated the influences of variable periods of voluntary wheel-running on the expression of basic fibroblast growth factor and its mRNA in various brain regions. Nuclease protection assays revealed that the hippocampus was the only region examined exhibiting changes in FGF-2 mRNA as a result of exercise. FGF-2 mRNA increased to reach a peak by the 4th night of wheel-running. FGF-2 immunoreactivity, normally located in the perinuclear area of astrocytes, following exercise became stronger and appeared to spread to the cytoplasm and processes of astrocytes. Quantification of the FGF-2-immunoreactive astrocytes showed an increase in density between 2 and 4 nights of running in discrete regions of the hippocampus. These results demonstrate that exercise regulates FGF-2 expression and suggest that growth factors are likely mediators of the positive effects of exercise on the brain.

Animals↗
PubMed2003

An inducible system for the study of FGF signalling in early amphibian development.

The use of a novel inducible FGF signalling system in the frog Xenopus laevis is reported. We show that the lipophilic, synthetic, dimerizing agent AP20187 is able to rapidly activate signalling through an ectopically expressed mutant form of FGFR1 (iFGFR1) in Xenopus embryos. iFGFR1 lacks an extracellular ligand binding domain and contains an AP20187 binding domain fused to the intracellular domain of mouse FGFR1. Induction of signalling by AP20187 is possible until at least early neurula stages, and we demonstrate that ectopically expressed iFGFR1 protein persists until late neurula stages. We show that activation of signalling through iFGFR1 can mimic a number of previously reported FGF activities, including mesoderm induction, repression of anterior development, and neural posteriorization. We show that competence to morphological posteriorization of the anteroposterior axis by FGF signalling only extends until about stage 10.5. We demonstrate that the competence of neural tissue to express the posterior markers Hoxa7 and Xcad3, in response to FGF signalling, is lost by the end of gastrula stages. We also show that activation of FGF signalling stimulates morphogenetic movements in neural tissue until at least the end of the gastrula stage.

Animals↗
PubMed2003

Pretreatment of donor cells with FGF-2 enhances survival of fetal hippocampal CA3 cell transplants in the chronically lesioned young adult hippocampus.

The lesioned CA3 region of the young adult hippocampus is very conducive for robust survival and integration of fetal hippocampal CA3 cell grafts when transplanted at an early postlesion delay of 4 days. However, similar CA3 cell grafts placed at 45 days postlesion display significantly diminished cell survival, implying that the receptivity of the lesioned young adult host hippocampus to grafts decreases considerably with a prolonged postlesion transplantation delay. We hypothesize that decreased cell survival in grafts placed into the chronically lesioned hippocampus is due to a reduced level of host neurotrophic factors that support fetal hippocampal cells; hence, pretreatment and grafting of donor fetal CA3 cells with fibroblast growth factor-2 (FGF-2) considerably enhances graft neuronal integration into the chronically lesioned young adult hippocampus. We employed the optical fractionator cell counting method and rigorously quantified the number of surviving cells and neurons derived from 5'-bromodeoxyuridine-labeled Embryonic Day 19 CA3 cell grafts pretreated and transplanted with FGF-2 into the lesioned CA3 region of the young adult rat hippocampus, at a delay of 60 days after a unilateral intracerebroventricular administration of the kainic acid. For comparison, we also analyzed the survival of standard fetal CA3 cell grafts (i.e., without FGF-2 treatment) after similar transplantation. Pre treatment and transplantation of CA3 cell grafts with FGF-2 resulted in a robust yield of surviving cells (115% of injected cells) and neurons (100% of injected cells) from grafts. In contrast, standard CA3 cell grafts exhibited a reduced yield of surviving cells (29%) and neurons (25%). Thus, the yield of neurons from fetal hippocampal CA3 cell grafts placed into the chronically lesioned young adult hippocampus can be greatly enhanced by a simple pretreatment and grafting of donor fetal CA3 cells with FGF-2. These results have significance toward advancement of clinically feasible cell grafting strategies for repair of the damaged young adult hippocampus, particularly at extended periods after the injury or the onset of neurodegenerative diseases.

Animals↗
PubMed2000

The high molecular weight isoforms of basic fibroblast growth factor (FGF-2): an insight into an intracrine mechanism.

Basic fibroblast growth factor (FGF-2) is an important modulator of cell growth and differentiation under both physiological and pathological conditions. Until recently, most investigations into the FGF-2 signalling pathway were concerned with its interaction with specific membrane receptors. Nevertheless, while a 18 kDa protein of FGF-2 is cytosolic, there are also co-translated high molecular weight (HMW) isoforms that are predominantly located in the cell nucleus. An increasing amount of data strongly argue in favour of distinct biological functions depending on the subcellular location of the FGF-2 species. This review describes the evidence concerning the strictly intracellular mode of action of the HMW isoforms of FGF-2.

Alternative Splicing↗
PubMed1998

Inhibition of FGF-1 receptor tyrosine kinase activity by PD 161570, a new protein-tyrosine kinase inhibitor.

Through direct synthetic efforts we discovered a small molecule which is a 40 nanomolar inhibitor of the human FGF-1 receptor tyrosine kinase. 1-Tert-butyl-3-[6-(2,6-dichloro-phenyl)-2-(4-diethylamino-butylamino)-py rido[2,3-d]pyrimidin-7-yl]-urea (PD 161570) had about 5- and 100-fold greater selectivity toward the FGF-1 receptor (IC50 = 40 nM) compared with the PDGFbeta receptor (IC50 = 262 nM) or EGF receptor (IC50 = 3.7 microM) tyrosine kinases, respectively. In addition, PD 161570 suppressed constitutive phosphorylation of the FGF-1 receptor in both human ovarian carcinoma cells (A121(p)) and Sf9 insect cells overexpressing the human FGF-1 receptor and blocked the growth of A121(p) cells in culture. The results demonstrate a novel synthetic inhibitor with nanomolar potency and specificity towards the FGF-1 receptor tyrosine kinase.

Animals↗
PubMed1992

FGF inactivates myogenic helix-loop-helix proteins through phosphorylation of a conserved protein kinase C site in their DNA-binding domains.

Myogenin belongs to a family of myogenic helix-loop-helix (HLH) proteins that activate muscle transcription through binding to a conserved DNA sequence associated with numerous muscle-specific genes. Fibroblast growth factor (FGF) inhibits myogenesis by inactivating myogenic HLH proteins. We show that activated protein kinase C (PKC) can substitute for FGF and inhibit transcriptional activity of myogenic HLH proteins. In transfected cells, FGF induces phosphorylation of a conserved site in the DNA-binding domain of myogenin. This site is phosphorylated by PKC in vivo and in vitro and mediates repression of the myogenic program through a loss in DNA binding activity. A myogenin mutant lacking the PKC phosphorylation site is not repressed by FGF, confirming this site as a molecular target for FGF-dependent repression of muscle transcription. These results establish a direct link between the signal transduction pathways that inhibit myogenesis and the transcription factors directly activating muscle-specific genes.

Amino Acid Sequence↗