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PubMed2002

Fgf genes in the basal chordate Ciona intestinalis.

In vertebrates, a number of fibroblast growth factors (FGFs) have been shown to play important roles in developing embryos and adult organisms. However, the molecular relationships of the vertebrate FGFs are not yet completely understood, partly due to the divergence of their amino acid sequences. To solve this problem, we have identified six FGF genes in a basal chordate, the ascidian Ciona intestinalis. A phylogenetic analysis confidently assigned two of them to vertebrate FGF8/17/18 and FGF11/12/13/14, respectively. Based on the presence of the conserved domains within or outside of the FGF domains, we speculate that three of the other genes are orthologous to vertebrate FGF3/7/10/22, FGF4/5/6 and FGF9/16/20, respectively, although we cannot assign the sixth member to any of the vertebrate FGFs. A survey of the raw whole genome shotgun sequences of C. intestinalis demonstrated the presence of no FGF genes other than the six genes in the genome. The identification of these six FGF genes in the basal chordate gave us an insight into the diversification of specific subfamilies of vertebrate FGFs.

Amino Acid Sequence↗
PubMed2000

Evolutionarily conserved and divergent expression of members of the FGF receptor family among vertebrate embryos, as revealed by FGFR expression patterns in Xenopus.

Fibroblast growth factors (FGFs) mediate many cell-cell signaling events during early development. While the actions of FGFs have been well-studied, the roles played by specific members of the FGF receptor (FGFR) family are poorly understood. To characterize the roles played by individual FGFRs we compared the regulation and expression of the three Xenopus FGFRs described to date (XFGFR-1, XFGFR-2, and XFGFR-4). First, we describe the expression of Xenopus FGFR-4; XFGFR-4 is present as a maternal mRNA and is found in the embryo through at least the tadpole stage. XFGFR-4 and XFGFR-1 mRNAs are present at comparable levels, arguing that both mediate FGF signaling during early development. Second, the expression of XFGFR-4 in animal caps differs from the expression of XFGFR-1 and XFGFR-2, suggesting that the FGFRs are independently regulated in ectoderm. Third, using whole-mount in situ hybridization, we show that XFGFR-1, XFGFR-2, and XFGFR-4 are expressed in dramatically different patterns, arguing that specific FGF signaling events are mediated by different members of the FGFR family. Among these, FGF signaling during the induction of neural crest cells is likely to be mediated by XFGFR-4. Comparison of our results with previously reported FGFR expression patterns reveals that FGFR-1 expression is highly conserved among vertebrate embryos, and FGFR-2 expression shows many features that are conserved and some that are divergent. In contrast, the expression pattern of FGFR-4 is highly divergent among vertebrate embryos.

Animals↗
PubMed1997

The multifunctionality of FGF-2 in the adrenal medulla.

Chromaffin cells of the adrenal medulla and their tumor counterparts, the pheochromocytoma (PC12) cells, are well-established model systems in neurobiology. The development of sympathoadrenal progenitor cells to chromaffin cells can be studied with regard to developmental signals which trigger the differentiation. With regard to potential treatments of neurological disorders like Parkinson's disease chromaffin cell grafting can be used as one therapeutical approach. The beneficial effect of chromaffin cell grafts is possibly not only related to the release of dopamine but may also be linked to the release of growth factors. One of the growth factors that is synthesized by chromaffin and PC12 cells is basic fibroblast growth factor (FGF-2). The experimental data available so far, are in agreement with different functional roles of FGF-2. This article summarizes the putative physiological functions of FGF-2 in the adrenal medulla. Three differential functional roles of FGF-2 are discussed: (1) as a differentiation factor for sympathoadrenal progenitor cells; (2) as a target-derived neurotrophic factor for preganglionic sympathetic neurons which innervate adrenal medullary cells; (3) as an auto-/paracrine factor in the adrenal medulla.

Adrenal Medulla↗
PubMed1987

Early and late mitogenic events induced by FGF on bovine epithelial lens cells are not triggered by hydrolysis of polyphosphoinositides.

Basic or acidic forms of FGF, a potent mitogen for Bovine Epithelial Lens cells caused a rapid and transient rise in cytoplasmic Ca2+ followed by an increase in intracellular pH of 0.4 units. When cells were labeled at equilibrium with [3H]-inositol, no significant breakdown of polyphosphoinositides (in the presence of 20 mM LiCl) could be detected in response to 10-100 ng/ml of FGF. Similarly, fetal calf serum efficiently reinitiated DNA synthesis in these cells with little stimulation of polyphosphoinositide hydrolysis. In contrast, prostaglandin F2 alpha and angiotensin II, two weak mitogens for BEL cells, were found potent agonists of polyphosphoinositide breakdown. These results strongly indicate that the mitogenic action of FGF is not coupled to phospholipase C activation, a conclusion consistent with the fact that the FGF-induced [Ca2+]i rise is strictly dependent upon external Ca2+.

Animals↗
PubMed1995

Stimulation of dopaminergic amacrine cells by stroboscopic illumination or fibroblast growth factor (bFGF, FGF-2) injections: possible roles in prevention of form-deprivation myopia in the chick.

Form-deprivation myopia (FDM) in the chick is a popular model for studying the postnatal regulation of ocular growth. Using this model, we have shown previously that dopamine and FGF-2 can counteract the effects of form-deprivation, thereby producing emmetropia. In the present study, we tested the hypothesis that the emmetropizing effects of flickering light and intraocular injections of FGF-2 in the chick are mediated by the activity of dopaminergic retinal amacrine cells. We have assessed the rate of dopamine synthesis in the retina by measuring the accumulation of 3,4-dihydroxyphenylalanine (DOPA). We found that form-deprivation reduces the rate of dopamine synthesis in the light-adapted retina, and that the normal rate of dopamine synthesis in the light can be restored by stroboscopic illumination at frequencies around 10 Hz. By labeling cells immunocytochemically we have shown that the synthesis of c-fos, a putative transcriptional regulator of the tyrosine hydroxylase gene, is induced in dopaminergic amacrine cells by stroboscopic illumination at around 10 Hz. These observations are consistent with a critical role for dopaminergic amacrine cells in the regulation of ocular growth by intermittent illumination. We have found also that intraocular injections of FGF-2 cause emmetropization without altering levels of expression of c-fos, amounts of tyrosine hydroxylase, or rates of dopamine synthesis with respect to vehicle-injected controls. We conclude that FGF acts either in parallel to or downstream from the dopaminergic amacrine cells, rather than through them. We observed that intravitreal injection per se induces high levels of c-fos expression in both form-deprived and non-deprived retinas, and causes partial emmetropization in form-deprived eyes, while inhibiting dopamine synthesis in non-deprived retinas. It is likely, therefore, that injection stimulates the production and/or release of unknown factors whose diverse effects on ocular growth and dopamine metabolism are mediated by complex pathways. Taken together, our results are consistent with the view that the retinal circuitry that controls postnatal ocular growth in the chick involves multiple messengers and pathways.

Animals↗
PubMed1990

Isolation of cDNAs encoding four mouse FGF family members and characterization of their expression patterns during embryogenesis.

To initiate a study of the role of the fibroblast growth factor (FGF) family in mammalian development, we have isolated cDNAs encoding four mouse FGF family members, aFGF, bFGF, kFGF, and FGF-5. This was achieved by a process that circumvents the use of cDNA libraries: for each family member, a cDNA fragment containing the conserved portion of the coding region was amplified from a pool of embryonic and teratocarcinoma cell cDNAs using the polymerase chain reaction (PCR) and cloned; the remaining coding sequences 5' and 3' to the conserved region were cloned using the RACE method. The cDNA clones obtained were used as probes to analyze the expression of these genes at the RNA level in teratocarcinoma cells and embryos at 10.5 to 17.5 days of gestation. Fgfk appears to be specific to undifferentiated teratocarcinoma stem cells. Fgf5 transcripts were detected at every stage and in every tissue tested, but showed a dramatic 15-fold increase in abundance as teratocarcinoma stem cells differentiated to simple embryoid bodies. Fgfb expression showed the greatest tissue-specific variability in abundance, with the highest levels detected in the developing limbs and tail. Fgfa showed the least variable pattern of expression, with transcripts detected at roughly equivalent levels in almost all samples analyzed. On the basis of these data we speculate on some possible roles that the different FGF family members may play in the developing embryo.

Amino Acid Sequence↗
PubMed1992

FGF-mediated aspects of skeletal muscle growth and differentiation are controlled by a high affinity receptor, FGFR1.

Fibroblast growth factors (FGFs) and FGF receptors (FGFRs) play major roles in vertebrate embryogenesis, including control of skeletal muscle growth and differentiation. Understanding their roles requires delineating the specific FGF and FGFR isoforms involved. This study analyzes the FGFR transcripts found in a model mouse skeletal myoblast cell line (MM14) during growth and terminal differentiation. MM14 cells express transcripts for FGFR1 (flg) but not FGFR2 (bek). The predominate FGFR1 transcript contains three immunoglobulin (Ig)-like domains in the extracellular ligand binding region. Approximately one-fourth of the three Ig-like domain transcripts possess a 6-nt deletion between the first and second Ig-like domains which after translation would result in deletion of an Arg-Arg pair. Cloning of mouse genomic DNA surrounding the region of the FGFR1 6-nt deletion indicates that the deletion is derived by alternative splicing of FGFR1 transcripts. Transcripts containing two Ig-like domains account for less than 5% of total FGFR1 mRNA in MM14 cells. A survey of RNA from mouse tissues indicated that two Ig-like domain FGFR1 transcripts are rare in all tissues except in lung, in which the two Ig-like domain form accounts for roughly 70% of the lung FGFR1 mRNA. PCR RACE cloning studies disclosed 162 nt of additional FGFR1 5'-flanking RNA which was highly GC-rich. FGFR1 transcripts decline 8- to 10-fold during low serum, (-)FGF-mediated differentiation of MM14 cultures. The kinetics of the FGFR1 mRNA decline is similar to the previously described differentiation-dependent decrease in cell surface FGF receptors.

Amino Acid Sequence↗
PubMed1993

Regulation by growth factors (IGF-I, b-FGF and TGF-beta) of proto-oncogene mRNA, growth and differentiation of bovine adrenocortical fasciculata cells.

Nuclear proto-oncoproteins have been implicated in the regulation of gene expression by peptidic hormones and growth factors during cell proliferation and differentiation. In the present study we have investigated in bovine adrenal cells (BAC) the effects of basic fibroblast growth factor (b-FGF), insulin-like growth factor 1 (IGF-I) and transforming growth factor beta (TGF-beta) on c-jun, jun-B and c-fos mRNA levels and on cell growth and differentiation. Factors able to enhance the three proto-oncogenes (IGF-I, b-FGF and angiotensin II (A-II)) stimulate cell growth, whereas those inhibiting cell growth (TGF-beta and ACTH) decrease c-jun mRNA level. These results suggest that expression of c-jun may be required to induce cell proliferation. The relation between proto-oncogenes and the expression of differentiated functions appears to be more complex. Whereas IGF-I, b-FGF and A-II increase the three nuclear proto-oncogenes, the effects of IGF-I and b-FGF on cytochrome P450 17 alpha-hydroxylase mRNA levels are opposite to those of A-II. On the other hand, while TGF-beta and A-II have inhibitory effects on P450 17 alpha mRNA level, they have opposite effects on c-jun mRNA.

Animals↗
PubMed1991

Expression of a dominant negative mutant of the FGF receptor disrupts mesoderm formation in Xenopus embryos.

Peptide growth factors may play a role in patterning of the early embryo, particularly in the induction of mesoderm. We have explored the role of fibroblast growth factor (FGF) in early Xenopus development by expressing a dominant negative mutant form of the FGF receptor. Using a functional assay in frog oocytes, we found that a truncated form of the receptor effectively abolished wild-type receptor function. Explants from embryos expressing this dominant negative mutant failed to induce mesoderm in response to FGF. In whole embryos the mutant receptor caused specific defects in gastrulation and in posterior development, and overexpression of a wild-type receptor could rescue these developmental defects. These results demonstrate that the FGF signaling pathway plays an important role in early embryogenesis, particularly in the formation of the posterior and lateral mesoderm.

Actins↗
PubMed1992

Responses of embryonic Xenopus cells to activin and FGF are separated by multiple dose thresholds and correspond to distinct axes of the mesoderm.

The potent mesoderm-inducing factors activin and FGF are present as maternally synthesized proteins in embryos of X. laevis. We show that activin can act on explanted blastomeres to induce at least five different cell states ranging from posterolateral mesoderm to dorsoanterior organizer mesoderm. Each state is induced in a narrow dose range bounded by sharp thresholds. By contrast, FGF induces only posterolateral markers and does so over relatively broad dose ranges. FGF can modulate the actions of activin, potentiating them and broadening the threshold-bounded dose windows. Our results indicate that orthogonal gradients of activin and FGF would be sufficient to specify the main elements of the body plan.

Activins↗
PubMed1994

Sonic hedgehog and Fgf-4 act through a signaling cascade and feedback loop to integrate growth and patterning of the developing limb bud.

Proper limb growth and patterning requires signals from the zone of polarizing activity in the posterior mesoderm and from the overlying apical ectodermal ridge (AER). Sonic hedgehog and Fgf-4, respectively, have recently been identified as candidates for these signals. We have dissected the roles of these secreted proteins in early limb development by ectopically regulating their activities in a number of surgical contexts. Our results indicate that Sonic hedgehog initiates expression of secondary signaling molecules, including Bmp-2 in the mesoderm and Fgf-4 in the ectoderm. The mesoderm requires ectodermally derived competence factors, which include Fgf-4, to activate target gene expression in response to Sonic hedgehog. The expression of Sonic hedgehog and Fgf-4 is coordinately regulated by a positive feedback loop operating between the posterior mesoderm and the overlying AER. Taken together, these data provide a basis for understanding the integration of growth and patterning in the developing limb.

Animals↗
PubMed1986

The brain fibroblast growth factor (FGF) is localized in neurons.

The physiological role of fibroblast growth factor (FGF), like many other characterized growth factors, is poorly understood. Therefore, it would be useful to know in which cell type this growth factor is present. Using monoclonal and polyclonal antibodies against FGF, we have localized this molecule in rat brain. Interestingly, FGF is found exclusively in neuronal cells. Since FGF stimulates the proliferation and maturation of glial cells in vitro, its involvement in the interaction between neuronal and glial cells in vivo is likely. A role in the triggering of reactive gliosis can also be hypothesized.

Animals↗
PubMed1989

Effects of IGF-I, rGH, FGF, EGF and NCS on DNA-synthesis, cell proliferation and morphology of chondrocytes isolated from rat rib growth cartilage.

The effects of IGF-I, rGH, FGF, EGF and NCS on DNA-synthesis were analyzed in resting, proliferative and hypertrophic chondrocytes obtained by fractionation. Proliferation and morphology were studied on non-fractionated cells. The highest stimulation of DNA-synthesis was induced by NCS followed by IGF-I at all stages of chondrocyte differentiation. DNA-synthesis was also stimulated by a low concentration of FGF (1 microgram/1) in proliferative and hypertrophic chondrocytes, while FGF in a higher concentration (10 micrograms/1) had no significant mitogenic effect. Cell proliferation was stimulated by both NCS and IGF-I, whereas FGF and EGF only caused morphological changes. Our data indicate that IGF-I is the main serum growth factor regulating growth and proliferation by interacting with chondrocytes at all stages of differentiation.

Animals↗
PubMed1990

A v-myc-immortalized sympathoadrenal progenitor cell line in which neuronal differentiation is initiated by FGF but not NGF.

Sympathetic neurons differentiate from a developmentally restricted progenitor cell in the neural crest-derived sympathoadrenal lineage. We have isolated these progenitors by fluorescence-activated cell sorting and immortalized them using a v-myc-containing retrovirus. The complement of antigenic markers expressed by these lines suggests that they have retained many of the properties of their normal counterparts. These lines initiate neuronal differentiation in response to basic FGF, but not to NGF, and do not contain NGF receptor mRNA. In NGF plus FGF, however, a small percentage of the cells differentiate to NGF-dependent postmitotic neurons. Furthermore, an induction of NGF receptor mRNA can be observed in response to FGF. Thus, the development of sympathetic neurons may involve a relay, in which FGF both initiates differentiation and induces the NGF receptor, which in turn controls further maturation and survival.

Animals↗
PubMed1990

Alternating phases of FGF receptor and NGF receptor expression in the developing chicken nervous system.

Patterns of expression of transcripts encoding receptors for fibroblast growth factor and nerve growth factor (FGF-R and NGF-R) in the developing chick nervous system are compared using in situ hybridization histochemistry. FGF-R transcripts are expressed abundantly in the germinal neuroepithelial layer. Expression ceases as cells migrate into the mantle layer and returns during late maturation of neuronal populations, including cholinergic nuclei of the basal forebrain, brainstem reticular and motor nuclei, and cerebellar Purkinje and granule neurons. The pattern of NGF-R expression is generally reciprocal to that of FGF-R in the CNS and in some phases of development of the PNS. These results suggest that FGF and NGF may act sequentially rather than in concert during neuronal development.

Animals↗
PubMed1995

Requirement for heparan sulphate proteoglycans to mediate basic fibroblast growth factor (FGF-2)-induced stimulation of Leydig cell steroidogenesis.

This study reports that, in contrast to previous findings, basic fibroblast growth factor (FGF-2) stimulates immature Leydig cell steroidogenesis in the absence of luteinizing hormone (LH). Heparan sulphate proteoglycans (HSPGs) are essential for this action of FGF-2 and the data suggest that HSPG/FGF-2 interactions have a significant role in the maintenance of immature Leydig cell steroidogenesis. Culture conditions were established for the maintenance of immature rat Leydig cells steroidogenesis in vitro for at least 2 days. Under these conditions the effect of exposure to FGF-2 at doses ranging from 0.1-10 ng/ml was shown to cause a significant stimulation of basal, but not LH-stimulated, 5 alpha-androstane 3 alpha,17 beta-diol production over 24h in culture. This stimulatory action on basal steroidogenesis is mediated through HSPG, as it was blocked by the addition of heparin (100 micrograms/ml), sodium chlorate (25mM) and protamine sulphate (5 micrograms/ml). These data demonstrate the involvement of HSPG in regulating FGF-2 action on Leydig cells and a potential role for Leydig cell HSPG in mediating paracrine regulatory actions of other heparin binding growth factors.

Animals↗
PubMed2005

A potency assay for a replication incompetent adenovirus type 5 carrying a human fgf-4 gene.

A bioassay that measures the potency of the FGF-4 transgene carried by a replication incompetent adenovirus type 5, Ad5FGF-4, was developed on ARPE-19 cells. The assay is carried out in a microtiter plate format and measures cellular proliferation following infection of ARPE-19 cells with a serial dilution of Ad5FGF-4. Proliferation is measured as a percentage increase in absorbance reading in relation to a mock-infected control. Ad5LacZ and Ad5FGF-4 viruses treated similarly to the test sample are included as negative and positive controls, respectively. The increased absorbance reading resulting from infection with the virus correlates with FGF-4 production as determined by an FGF-4 enzyme-linked immunosorbent assay, an increase in de novo DNA synthesis as measured by BrdU incorporation, and an increase in the total cell number. The assay shows a dose-dependent response and is capable of evaluating the stability of Ad5FGF-4. A sample being tested is compared with a reference standard, and the relative potency value is obtained by a parallel line analysis of the dose-response curve of the test article in relation to the reference standard. Therefore, this procedure can be used as an in vitro efficacy-indicating assay, demonstrating that the FGF-4 transgene product carried by Ad5FGF-4 is biologically active.

Adenoviridae↗
PubMed2004

FGF-23 transgenic mice demonstrate hypophosphatemic rickets with reduced expression of sodium phosphate cotransporter type IIa.

Fibroblast growth factor (FGF)-23 was identified as a causative factor of tumor-induced osteomalacia and also as a responsible gene for autosomal dominant hypophosphatemic rickets. To clarify the pathophysiological roles of FGF-23 in these diseases, we generated its transgenic mice. The transgenic mice expressing human FGF-23 reproduced the common clinical features of these diseases such as hypophosphatemia probably due to increased renal phosphate wasting, inappropriately low serum 1,25-dihydroxyvitamin D level, and rachitic bone. The renal phosphate wasting in the transgenic mice was accompanied by the reduced expression of sodium phosphate cotransporter type IIa in renal proximal tubules. These results reinforce the notion that the excessive action of FGF-23 plays a causative role in the development of several hypophosphatemic rickets/osteomalacia.

Animals↗