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PubMed1995

Expression of a truncated FGF receptor results in defective lens development in transgenic mice.

Members of the fibroblast growth factor (FGF) family are thought to initiate biological responses through the activation of cell surface receptors which must dimerize to transmit an intracellular signal. Mammalian lens epithelial cells respond to exogenous extracellular FGF, either in tissue culture or in transgenic mice, by initiating fiber cell differentiation. The role of FGF signalling in normal lens development was evaluated by lens-specific synthesis of a kinase-deficient FGF receptor type I (FGFR1) in transgenic mice. This truncated FGF receptor is thought to act as a dominant negative protein by heterodimerization with endogenous FGF receptors. The presence of transgenic mRNA in the lens was confirmed by in situ hybridization and by polymerase chain reaction amplification of reverse transcribed lens RNA (RT-PCR). The presence of transgenic protein was determined by Western blotting with antibodies to an extracellular domain of FGFR1. Three of four transgenic families expressing the truncated FGF receptor exhibited lens defects ranging from cataracts to severe microphthalmia. While the microphthalmic lenses displayed a normal pattern of differentiation-specific crystallin expression, the lens epithelial cells were reduced in number and the lens fiber cells displayed characteristics consistent with the induction of apoptosis. Our results support the view that FGF receptor signalling plays an essential role in normal lens biology.

Animals↗
PubMed1996

A truncated FGF receptor blocks neural induction by endogenous Xenopus inducers.

We have examined the role of fibroblast growth factor (FGF) signalling in neural induction. The approach takes advantage of the fact that both noggin and the dominant negative mutant activin receptor (delta1XAR1) directly induce neural tissues in the absence of dorsal mesoderm. A truncated FGF receptor (XFD) is co-expressed with noggin or delta1XAR1 in both whole embryos and isolated animal caps. We demonstrate that inhibition of FGF signalling prevents neural induction by both factors. Furthermore, neural induction by organizers (the dorsal lip of blastopore and Hensen's node) is also blocked by inhibiting FGF signalling in ectoderm. It has been proposed that the specification of anterior neuroectoderm, including the cement gland, occurs in a sequential manner as gastrulation proceeds. We show that the specification of the most anterior neuroectoderm by noggin may occur before gastrulation and does not require FGF signalling, since both the cement gland marker XCG-1 and the anterior neural marker Otx-2 are normally expressed in ectodermal explants co-injected with noggin and XFD RNAs, but the cement gland cells are poorly differentiated. In contrast, the expression of both genes induced by CSKA.noggin, which is expressed after the mid-blastula transition, is strongly inhibited by the presence of XFD. Therefore the noggin-mediated neural induction that takes place at gastrula stages is abolished in the absence of FGF signalling. Since inhibition of FGF signalling blocks the neuralizing effect of different neural inducers that function through independent mechanisms, we propose that FGF receptor-related-signalling is required for the response to inducing signals of ectodermal cells from gastrula.

Activin Receptors↗
PubMed2001

FGF-induced lens cell proliferation and differentiation is dependent on MAPK (ERK1/2) signalling.

Members of the fibroblast growth factor (FGF) family induce lens epithelial cells to undergo cell division and differentiate into fibres; a low dose of FGF can stimulate cell proliferation (but not fibre differentiation), whereas higher doses of FGF are required to induce fibre differentiation. To determine if these cellular events are regulated by the same signalling pathways, we examined the role of mitogen-activated protein kinase (MAPK) signalling in FGF-induced lens cell proliferation and differentiation. We show that FGF induced a dose-dependent activation of extracellular regulated kinase 1/2 (ERK1/2) as early as 15 minutes in culture, with a high (differentiating) dose of FGF stimulating a greater level of ERK phosphorylation than a lower (proliferating) dose. Subsequent blocking experiments using UO126 (a specific inhibitor of ERK activation) showed that activation of ERK is required for FGF-induced lens cell proliferation and fibre differentiation. Interestingly, inhibition of ERK signalling can block the morphological changes associated with FGF-induced lens fibre differentiation; however, it cannot block the synthesis of some of the molecular differentiation markers, namely, beta-crystallin. These findings are consistent with the in vivo distribution of the phosphorylated (active) forms of ERK1/2 in the lens. Taken together, our data indicate that different levels of ERK signalling may be important for the regulation of lens cell proliferation and early morphological events associated with fibre differentiation; however, multiple signalling pathways are likely to be required for the process of lens fibre differentiation and maturation.

Animals↗
PubMed2006

Localization of FGF-6 and FGFR-4 during prenatal and early postnatal development of the mouse sublingual gland.

A number of fibroblast growth factors (FGFs) are involved in regulatory mechanisms of the salivary gland development. However, the role of FGF-6 unique in myogenic cells has not been elucidated in the developing sublingual gland. In the present study, temporo-spatial expression of FGF-6 and its receptor (FGFR)-4, in conjunction with some related histo-chemical properties, were investigated in the sublingual gland of the prenatal and early postnatal mice. The earliest expression of both FGF-6 and FGFR-4 was detected in immature acinar cells at gestational day 17 (GD17). The staining intensity increased gradually and some acinar cells showed a distinct staining at postnatal day 0 (PD0). The immunopositive cells had a relatively round profile and were assumed to be acinar cells. The positive staining decreased thereafter and disappeared completely by PD11. To confirm the identity of cells positive for FGF-6, double immunolabeling with anti-alphasmooth muscle actin (alphaSMA) and anti-FGF-6 antibodies was performed. The positive staining of alphaSMA, a marker of myoepithelial cells, was detected in the flattened cells surrounding the acini but not in the cells positive for FGF-6. The staining properties of secretory granules in acinar cells were also examined with periodic acid-Shiff (PAS) and alcian blue (AB). PAS-positive granules abundant in the late gestational stages (GD17 to PD0) began to be replaced with AB-positive mucous granules at early neonatal days (PD0-3), when the FGF-6/FGFR-4 expression was the strongest. These findings suggest that FGF-6/FGFR-4 might be involved in the changes of secretory granule content of acinar cells in the sublingual gland during the late gestational and early neonatal stages.

Animals↗
PubMed2006

Glypican-1 is frequently overexpressed in human gliomas and enhances FGF-2 signaling in glioma cells.

Signaling by fibroblast growth factor 2 (FGF-2), an autocrine stimulator of glioma growth, is regulated by heparan sulfate proteoglycans (HSPGs) via a ternary complex with FGF-2 and the FGF receptor (FGFR). To characterize glioma growth signaling, we examined whether altered HSPGs contribute to loss of growth control in gliomas. In a screen of five human glioma cell lines, U118 and U251 cell HSPGs activated FGF-2 signaling via FGFR1c. The direct comparison of U251 glioma cells with normal astrocyte HSPGs demonstrated that the glioma HSPGs had a significantly elevated ability to promote FGF-2-dependent mitogenic signaling via FGFR1c. This enhanced activity correlated with a higher level of overall sulfation, specifically the abundance of 2S- and 6S-containing disaccharides. Glioma cell expression of the cell-surface HSPG glypican-1 closely mirrored the FGF-2 coactivator activity. Furthermore, forced expression of glypican-1 in (glypican-1-deficient) U87 glioma cells enhanced their FGF-2 response. Immunohistochemical analysis revealed a highly significant overexpression of glypican-1 in human astrocytoma and oligodendroglioma samples compared with nonneoplastic gliosis. In summary, these observations suggest that altered HSPGs contribute to enhanced signaling of FGF-2 via FGFR1c in gliomas with glypican-1 playing a significant role in this mitogenic pathway.

Animals↗
PubMed2000

Retinal degeneration is slowed in transgenic rats by AAV-mediated delivery of FGF-2.

PURPOSE: We evaluated adeno-associated virus (AAV)-mediated gene transfer of basic fibroblast growth factor (FGF-2) as a therapy for photoreceptor degeneration in a transgenic rat model of retinitis pigmentosa. METHODS: Recombinant adeno-associated virus vector (rAAV) incorporating a constitutive cytomegalovirus (CMV) promoter was used to transfer the bovine FGF-2 gene to photoreceptors. AAV was administered by subretinal injection to transgenic rats (TgN S334ter-4) at postnatal day 15 (P15). Control eyes were uninjected, injected with PBS, or AAV-LacZ. Eyes were examined by histopathology, morphometric analysis, and electroretinography at P60. RESULTS: Expression of recombinant FGF-2 slowed the rate of photoreceptor degeneration. Morphologic studies demonstrated significantly more photoreceptors surviving in eyes injected with AAV-FGF-2 than in controls. Insignificant rescue effects were seen in retinas injected with buffer only. No significant inflammatory response or neovascularization was detected. Electroretinographic (ERG) responses of eyes injected with AAV-FGF-2 were increased compared with uninjected eyes; however, these amplitudes were not significantly larger than eyes receiving an AAV-LacZ control vector. CONCLUSIONS: Transduction of retinal cells with AAV-FGF-2 reduces the rate of photoreceptor degeneration in an S334ter-4 animal model. Despite the lack of significantly increased ERG amplitudes from eyes expressing FGF-2, a greater number of surviving photoreceptors was demonstrated. Delivery of FGF-2 using recombinant AAV has potential as a therapy for retinal degeneration.

Animals↗
PubMed2000

Differential expression of FGF receptors and of myogenic regulatory factors in primary cultures of satellite cells originating from fast (EDL) and slow (Soleus) twitch rat muscles.

In the rat, the fast and slow twitch muscles respectively Extensor digitorum longus (EDL) and Soleus present differential characteristics during regeneration. This suggests that their satellite cells responsible for muscle growth and repair represent distinct cellular populations. We have previously shown that satellite cells dissociated from Soleus and grown in vitro proliferate more readily than those isolated from EDL muscle. Fibroblast growth factors (FGFs) are known as regulators of myoblast proliferation and several studies have revealed a relationship between the response of myoblasts to FGF and the expression of myogenic regulatory factors (MRF) of the MyoD family by myoblasts. Therefore, we presently examined the possibility that the satellite cells isolated from EDL and Soleus muscles differ in the expression of FGF receptors (FGF-R) and of MRF expression. FGF-R1 and -R4 were strongly expressed in proliferating cultures whereas FGF-R2 and R3 were not detected in these cultures. In differentiating cultures, only -R1 was present in EDL satellite cells while FGF-R4 was also still expressed in Soleus cells. Interestingly, the unconventional receptor for FGF called cystein rich FGF receptor (CFR), of yet unknown function, was mainly detected in EDL satellite cell cultures. Soleus and EDL satellite cell cultures also differed in the expression MRFs. These results are consistent with the notion that satellite cells from fast and slow twitch muscles belong to different types of myogenic cells and suggest that satellite cells might play distinct roles in the formation and diversification of fast and slow fibres.

Animals↗
PubMed1992

Angiogenic activity of the K-fgf/hst oncogene in neural transplants.

Using retrovirus-mediated gene transfer into neural transplants, we have expressed the human K-fgf/hst oncogene in the central nervous system. Single-cell suspensions of fetal rat brains were removed at embryonic days 13 and 14, exposed to a retroviral vector encoding the K-fgf oncogene and stereotaxically implanted into the caudate putamen of syngenic adult Fisher rats. Recipient animals were sacrificed at intervals of 6-16 months without evidence of neurological impairment. Mock-infected grafts showed the characteristic histopathological appearance of organotypically differentiated neural transplants. In contrast, grafts exposed to the K-fgf gene exhibited abundant capillary proliferation and capillary angiomas. By in situ hybridization analysis and immunohistochemistry, expression of K-fgf was detected in neural cells adjacent to vascular proliferations. Neurons and glia with abundant K-fgf transcripts were morphologically unaffected. In order to examine the transforming potential of the K-fgf gene in the nervous system, we combined retrovirus-mediated transfer of the K-fgf oncogene with a single transplacental exposure of the donor animals to the neurotropic carcinogen N-ethyl-N-nitrosourea (NEU). However, this combination of transforming agents did not result in tumor formation in the grafts. These results provide evidence for a powerful angiogenic effect of K-fgf on the developing brain in vivo.

Animals↗
PubMed2004

FGF-2 counteracts loss of TGFbeta affected cells from rat lens explants: implications for PCO (after cataract).

PURPOSE: While cataract surgery initially benefits most patients, many suffer secondary loss of vision because of posterior capsule opacification (PCO). Lens epithelial cells left behind at surgery become aberrant and migrate into the light path. TGF-beta (TGFbeta) appears to play a key role in this process by inducing the cells to undergo an epithelial-mesenchymal transition. Paradoxically, it also typically induces them to undergo apoptotic death. The present study was undertaken to investigate the hypothesis that FGF plays a role in PCO formation by promoting the survival of abnormal cells with PCO-like characteristics. METHODS: Rat lens epithelial explants were cultured for one day with TGFbeta2 (25-100 pg/ml) then in control medium with or without FGF-2 (5-100 ng/ml) for up to 31 days, with assessment by light and scanning electron microscopy and immunolocalization. RESULTS: Survival of TGFbeta treated cells was promoted by FGF-2 but not by EGF, PDGF, IGF, or HGF. In the absence of FGF virtually all cells were lost from explants within 5 days. However, when FGF was included cells remained viable throughout culture. These cells, which no longer expressed the lens epithelial marker Pax6, exhibited immunoreactivity for non-lens cell proteins associated with PCO (alpha-smooth muscle actin, type I collagen, and fibronectin) and also beta-crystallin. FGF inclusion also promoted ECM production, multilayering, and plaque formation, features of PCO known to contribute to visual loss. CONCLUSIONS: This study points to a key role for FGF in the etiology of PCO and suggests that FGF inhibitors may be useful in preventing PCO.

Actins↗
PubMedDate not supplied

Influence of hepatocyte growth factor/scatter factor (HGF/SF) on fibroblast growth factor-2 (FGF-2) levels in external auditory canal cholesteatoma (EACC) cell culture.

BACKGROUND: In previous studies, we cited circulatory disorders and hypoxia as etiological factors for the formation of external auditory canal cholesteatoma (EACC) resulting in angiogenesis. Here, we investigate how the angiogenic factor hepatocyte growth factor/scatter factor (HGF/SF) influences the level of another angiogenic factor FGF-2. MATERIALS AND METHODS: After 16 to 72 hours of incubation with 20 ng/ml HGF/SF, levels of VEGF in the HGF/SF-treated and untreated culture was analyzed. We also investigated the influence of HGF/SF (20-80 ng/ml) on the concentration of FGF-2. RESULTS: After 16 hours of incubation with HGF/SF at 20 ng/ml, FGF-2 was measured at 44.19 pg/ml (control: 42.24 pg/ml). After 72 hours, FGF-2 was at 23.41 pg/ml (control: 14.83 pg/ml). After 24 hours, 40 ng/ml HGF/SF showed the highest concentration of FGF-2. CONCLUSION: FGF-2 levels were initially elevated after treatment with HGF/SF, however, further incubation did not show any increase. We assume that HGF/SF released FGF-2 in the matrix but did not induce FGF-2 expression. The most effective HGF/SF concentration was 40 ng/ml.

Angiogenic Proteins↗
PubMed1989

Expression of the K-fgf protooncogene is repressed during differentiation of F9 cells.

Utilizing F9 embryonal carcinoma cells as a model system for early mammalian development, we have studied the pattern of expression of the endogenous murine homolog of the human K-fgf/hst oncogene, which encodes a new member of the fibroblast growth factors (FGFs) family. The K-fgf mRNA is expressed in undifferentiated F9 cells and its level becomes undetectable upon the induction of differentiation. Furthermore, a growth-promoting activity with properties identical to those of K-FGF is present in the conditioned medium of F9 cells, but absent in that of differentiated cells. Shut-off of K-fgf expression is mediated at the transcriptional level. The acidic FGF gene is also expressed in undifferentiated F9 cells and down modulated once differentiation is induced. In contrast, int-2, another member of the FGF gene family, is transcriptionally induced in differentiated F9 cells. Our data suggest that single members of the FGF gene family may perform distinct functions in vivo, and that the physiological role of K-FGF may be related to early development.

Cell Differentiation↗
PubMed1997

Endogenous FGF-2 is important for cholinergic sprouting in the denervated hippocampus.

To investigate the molecular mechanisms of cholinergic sprouting in the hippocampus after removal of entorhinal cortical inputs, we evaluated trophic factor gene expression in the denervated hippocampus. Despite the proposed role for nerve growth factor (NGF) in this sprouting, we observed no change in NGF mRNA or protein at several postlesion time points. In contrast, FGF-2 mRNA was increased within 16 hr. FGF-2 immunoreactivity was localized within GFAP-positive hypertrophic astrocytes distributed specifically within the denervated outer molecular layer after the lesion. To address the functional significance of this increase in FGF-2, we assessed the magnitude of cholinergic sprouting in animals receiving chronic intracerebroventricular infusions of neutralizing antibodies specific for FGF-2 and compared it with that observed in lesioned animals receiving infusate controls. Animals given FGF-2 antibodies displayed a marked reduction in cholinergic sprouting as compared with controls. In fact, many of these animals exhibited virtually no sprouting at all despite histological verification of complete lesions. These results suggest that endogenous FGF-2 promotes cholinergic axonal sprouting in the injured adult brain. Furthermore, immunocytochemical localization of receptors for FGF-2 (i.e., FGFR1) on projecting basal forebrain cholinergic neurons suggests that FGF-2 acts directly on these neurons to induce the lesion-induced sprouting response.

Animals↗
PubMed1997

Antiestrogenic compounds inhibit estrogen-induced expression of fibroblast growth factor family (FGF-1, 2, and 4) mRNA in well-differentiated endometrial cancer cells.

To clarify the effect of sex steroids on neovascularization in the growth, invasion and metastasis of endometrial cancer, the regulations of acid fibroblast growth factor (FGF-1), basic FGF (FGF-2) and hst-1 (FGF-4) mRNA expressions were studied in well-differentiated endometrial cancer cells under the influence of sex steroids. The levels of FGF-1 and 2 mRNAs in the well-differentiated endometrial cancer (Ishikawa) cells were significantly increased by estradiol. This increase was significantly inhibited by progestins (progesterone, medroxyprogesterone acetate [MPA] and 17 alpha-hydroxyprogesterone) and tamoxifen, but not by tetrahydrocortisol, hydrocortisone and danazol. The expression of FGF-4 mRNA was not altered by sex steroids. Therefore, estrogen might stimulate FGF-2 with FGF-1 secretion of endometrial cancer cells for neovascularization, and antiestrogenic compounds do inhibit estrogen-induced events.

Adenocarcinoma↗
PubMed2000

Angioblast differentiation is influenced by the local environment: FGF-2 induces angioblasts and patterns vessel formation in the quail embryo.

The embryonic vasculature forms by the segregation, migration, and assembly of angioblasts from mesoderm, a process termed vasculogenesis. The initial role of fibroblast growth factor 2 (FGF-2) in vascular development appears to be in the induction of endothelial precursors, angioblasts. Quail somites transplanted into chick embryos will give rise to angioblasts of quail origin. The number of angioblasts present within the chimera is dependent on the host environment. Angioblast induction can be demonstrated in vitro by the addition of FGF-2 to cultures of dissociated somitic mesoderm, as assessed by QH-1 epitope expression. Manipulation of FGF-2 concentration in the quail/chick chimeras by FGF-2 peptide or neutralizing antibody injections increases or decreases angioblast induction in the predicted manner. To better control growth factor release in vivo we have implanted beads that release FGF-2 into the embryonic environment. FGF-2 beads implanted into the somite induce angioblast differentiation in the epithelial somite; whereas, beads lateral to the somitic mesoderm induce the formation of ectopic vessels. These studies suggest that FGF-2 is important for both the induction of angioblasts and the assembly of angioblasts into the initial vasculature pattern.

Animals↗
PubMed1996

Basic fibroblast growth factor (FGF-2) protects rat cochlear hair cells in organotypical culture from aminoglycoside injury.

Given the evidence that basic fibroblast growth factor (FGF-2) can protect neural and retinal cells from degeneration, we evaluated the potential of this growth factor to protect sensory cells in the inner ear. When sensory cells of the organ of Corti are exposed to aminoglycoside antibiotics such as neomycin either in vivo or in vitro, significant ototoxicity is observed. The in vitro cytotoxic effects of neomycin are dose and time dependent. In neonatal rat organ of Corti cultures, complete inner and outer hair cell destruction is observed at high (mM) concentrations of neomycin while inner hair cell survival and severely damaged outer hair cells are noted at moderate (microM) concentrations, with a maximal effect observed after 2 days of culture. Approximately 50% of cochlear outer hair cells are lost at a dose of 35 microM neomycin, and most surviving cells show disorganized stereocilia. Inner hair cells show primarily disorganization of their stereocilia. A significant protective effect is observed when the organ of Corti is pre-treated with FGF-2 (500 ng/ml) for 48 hours, and then FGF-2 is included with neomycin in the culture medium. A greater extent of outer hair cell survival and a significant decrease in stereociliary damage are noted with FGF-2. However, disorganization of inner hair cell stereocilia is unaffected by FGF-2. The protective effect of FGF-2 is specific, since interleukin-1B, nerve growth factor, tumor necrosis factor, and epidermal growth factor are ineffective, while retinoic acid and transforming growth factor alpha show only a moderate protective effect. These results confirm the potential of molecules like FGF-2 for preventing cell death due to a variety of causes.

Animals↗
PubMed1996

Binding of transcription factors to widely-separated cis-regulatory elements of the murine FGF-4 gene.

Embryonal carcinoma (EC) cells and their embryo-derived counterparts, embryonic stem (ES) cells, have been used extensively to study the transcriptional regulation of the fibroblast growth factor-4 (FGF-4) gene. The FGF-4 gene is expressed in EC cells and ES cells, but it is repressed in their retinoic acid (RA)-induced differentiated counterparts. Previous studies have shown that the transcription of the FGF-4 gene is controlled by cis-regulatory elements located in the 5' flanking region of the gene, and by a powerful enhancer located approximately 3 kb downstream from the transcription start site. In the current study, gel mobility shift analysis was used to examine the binding of nuclear proteins to cis-regulatory elements involved in the transcription of the FGF-4 gene. We demonstrate that the transcription factors Sp1 and Sp3 in nuclear extracts prepared from EC cells bind to three Sp1 motifs, one located in the downstream enhancer, and two located in the 5' flanking region of the gene. We also show that Sp1 and Sp3 bind to each of the Sp1 motifs when nuclear extracts prepared from EC-derived differentiated cells are used. In contrast, differentiation of EC cells and ES cells drastically reduces the ability of nuclear factors to bind to an octamer motif and an adjacent High Mobility Group (HMG) motif, which have been shown previously to play essential roles in the functioning of the FGF-4 enhancer. Together, these findings provide a mechanistic explanation of how the distant FGF-4 enhancer promotes transcription of this gene in EC cells and ES cells, and how differentiation of these cells represses transcription of the FGF-4 gene.

Animals↗
PubMed1998

Role of the transcription factor Sox-2 in the expression of the FGF-4 gene in embryonal carcinoma cells.

It has been shown previously that the FGF-4 gene is regulated by a powerful downstream enhancer in embryonal carcinoma (EC) cells. This enhancer contains an essential HMG motif; however, the transcription factor that binds to the HMG motif in EC cells has not been determined definitively. In earlier studies, this HMG motif was shown to bind a heat-stable, redox-insensitive factor expressed by F9 EC cells. Others have proposed that the transcription factor Sox-2 binds to the FGF-4 enhancer HMG motif. In this study, we demonstrate that the N-terminal half of Sox-2, which contains the DNA binding domain, binds to the FGF-4 enhancer HMG motif and we show that this binding is unaffected by heat and oxidation. In addition, we employed two experimental approaches to demonstrate that Sox-2 regulates the transcription of the FGF-4 gene in EC cells. As part of these studies, an expression plasmid that codes for a dominant-negative form of Sox-2 was used in transient expression assays. In other experiments, a Sox-2 antisense expression plasmid was used. When co-transfected into F9 EC cells along with an FGF-4 promoter/reporter gene construct, each expression plasmid caused a significant reduction in reporter activity. Our studies also demonstrate that Sox-2 affects the expression of the FGF-4 gene in the multipotent EC cell line, P19. Taken together, these studies argue strongly that Sox-2 plays an important role in the expression of the FGF-4 gene in vivo.

Animals↗
PubMed1998

Responsiveness of developing dental tissues to fibroblast growth factors: expression of splicing alternatives of FGFR1, -2, -3, and of FGFR4; and stimulation of cell proliferation by FGF-2, -4, -8, and -9.

To elucidate the roles of fibroblast growth factors (FGF) in tooth development, we have analyzed the expression patterns of fibroblast growth factor receptors (FGFR) in mouse teeth by in situ hybridization and studied the effects of FGF-2, -4, -8, and -9 on cell proliferation in vitro by local application with beads on isolated dental mesenchymes. mRNAs of FGFR-1, -2, and -3 were localized by probes specific for the alternative splice variants IIIb and IIIc. The expression patterns of FGFR1 -2, and -3 were completely different, and the two splicing variants of FGFR1 and 2 exhibited different expression domains. FGFR4 was not expressed in the developing teeth. The IIIb splice forms of FGFR1 and -2 were expressed in the dental epithelium during morphogenesis. The IIIc splice form of FGFR1 was expressed both in epithelium and mesenchyme whereas FGFR2 IIIc was confined to the mesenchymal cells of the dental follicle. Both splice forms of FGFR3 were expressed in dental papilla mesenchyme. None of the FGF-receptors was detected in the primary enamel knot, the putative signaling center regulating tooth morphogenesis. This may explain the fact that enamel knot cells do not proliferate, although they express intensely mitogenic FGFs. Beads releasing FGF-2, -4, -8, or -9 proteins stimulated cell proliferation in cultured dental mesenchymes. These data, together with our earlier data on FGF expression [Kettunen and Thesleff (1998): Dev Dyn 211:256-268] suggest that FGF-8 and -9 mediate epithelial-mesenchymal interactions during tooth initiation. During advancing morphogenesis FGF-3, -4, and -9 may act both on mesenchyme and epithelium. Finally, the intense expression of FGFR1 in odontoblasts and ameloblasts and FGFR2 IIIb in ameloblasts suggests that FGFs participate in regulation of their differentiation and/or secretory functions.

Alternative Splicing↗