Expression of rat fibroblast growth factor receptor 1 as three splicing variants during kidney development

1993 ◽  
Vol 264 (1) ◽  
pp. F66-F73
Author(s):  
E. G. Kim ◽  
H. M. Kwon ◽  
C. R. Burrow ◽  
B. J. Ballermann
Keyword(s):  
Kidney Development ◽  
Rat Kidney ◽  
Cdna Probe ◽  
Growth Factor Receptor ◽  
Neonatal Rat ◽  
Fibroblast Growth ◽  
Fgf Receptor ◽  
Produce Cell ◽  
Splicing Variant ◽  
Splicing Variants

Fibroblast growth factors (FGF) are known to participate in the processes of embryogenesis and angiogenesis. This study was undertaken to examine the transcriptional and posttranscriptional regulation of the FGF receptor 1 (FGFR-1) subclass in the embryonic rat kidney. Two full-length FGF receptor cDNAs were cloned using low-stringency screening of a neonatal rat kidney library with a chicken FGFR-1 cDNA probe. Sequencing revealed these cloned cDNAs to be rat homologues of the FGFR-1 subtype, with the two clones representing splicing variants beta and gamma of the FGFR-1. Evidence for renal expression of a third splicing variant (alpha) was obtained by use of the polymerase chain reaction. Splicing variants alpha and beta of FGFR-1 are predicted to produce cell-surface FGF receptors with three and two immunoglobulin-like domains, respectively, whereas the gamma-isoform may represent an intracellular form of the receptor. Although all three splicing variants were expressed in the developing kidney at days 14, 17, and 20 of gestation, at neonatal days 1 and 7 and in mature rats the beta-isoform was present in vastly larger abundance than alpha- and gamma-isoforms at all stages studied. Northern blot analysis revealed enhanced expression of FGFR-1 in the neonatal compared with the mature kidney. It is concluded that FGFR-1 is expressed in the kidney predominantly as the beta-isoform splicing variant and that expression of this receptor is enhanced during kidney development.

Differential expression of transforming growth factor-beta receptors in rat kidney development

1997 ◽  
Vol 273 (3) ◽  
pp. F386-F395 ◽  
Author(s):  
M. E. Choi ◽  
A. Liu ◽  
B. J. Ballermann
Keyword(s):  
Transforming Growth Factor Beta ◽  
Kidney Development ◽  
Transforming Growth Factor ◽  
Rat Kidney ◽  
Neonatal Rat ◽  
Tgf Beta ◽  
Adult Rat ◽  
Beta Receptors ◽  
Growth Factor Beta ◽  
Alk 5

Transforming growth factor-beta 1 (TGF-beta 1) is strongly expressed during embryogenesis and in sites undergoing intense development and morphogenesis. Two receptor serine/threonine kinases (types I and II) have been identified as signal-transducing TGF-beta receptors. This study was undertaken to further explore the role of the distinct TGF-beta receptors during kidney development. The species-specific sequence information for the two T beta R-I, namely, activin receptor-like kinase-5 (ALK-5) and Tsk7L, in the rat was sought. Two full-length T beta R-I cDNAs were cloned from a neonatal rat kidney and lung libraries, and sequencing revealed that they were the rat homologs of human ALK-5 and murine Tsk7L. Both types I and II TGF-beta receptors are expressed in the kidney as determined by Northern blot analysis. T beta R-II mRNA abundance was significantly greater in the neonatal rat kidney compared with the adult rat kidney. Similarly, ALK-5 mRNA was more highly expressed in the fetal and neonatal rat kidney than the adult rat kidney. In contrast, there was no significant difference in Tsk7L mRNA abundance among the fetal, neonatal, and adult rat kidney. Thus, based on these findings, both T beta R-II and ALK-5 are developmentally regulated in the kidney. Increased expression of T beta R-II and ALK-5 proteins in the developing kidney was confirmed by immunohistochemistry. Interestingly, the two TGF-beta receptors did not entirely colocalize, raising the intriguing possibility that other TGF-beta signaling receptors may be involved.

scholarly journals Fibroblast Growth Factor Receptor-Mediated Rescue of x-Ephrin B1-Induced Cell Dissociation in XenopusEmbryos

2000 ◽  
Vol 20 (2) ◽  
pp. 724-734 ◽  
Author(s):  
Lisa D. Chong ◽  
Eui Kyun Park ◽  
Erin Latimer ◽  
Robert Friesel ◽  
Ira O. Daar
Keyword(s):  
Cell Adhesion ◽  
Growth Factor ◽  
Fibroblast Growth Factor ◽  
Tyrosine Kinases ◽  
Growth Factor Receptor ◽  
Fibroblast Growth ◽  
Fgf Receptor ◽  
Cell Adhesion And Migration ◽  
Membrane Bound ◽  
And Migration

ABSTRACT The Eph family of receptor tyrosine kinases and their membrane-bound ligands, the ephrins, have been implicated in regulating cell adhesion and migration during development by mediating cell-to-cell signaling events. Genetic evidence suggests that ephrins may transduce signals and become tyrosine phosphorylated during embryogenesis. However, the induction and functional significance of ephrin phosphorylation is not yet clear. Here, we report that when we used ectopically expressed proteins, we found that an activated fibroblast growth factor (FGF) receptor associated with and induced the phosphorylation of ephrin B1 on tyrosine. Moreover, this phosphorylation reduced the ability of overexpressed ephrin B1 to reduce cell adhesion. In addition, we identified a region in the cytoplasmic tail of ephrin B1 that is critical for interaction with the FGF receptor; we also report FGF-induced phosphorylation of ephrins in a neural tissue. This is the first demonstration of communication between the FGF receptor family and the Eph ligand family and implicates cross talk between these two cell surface molecules in regulating cell adhesion.

The fibroblast growth factor receptor, FGFR3, forms gradients of intact and degraded protein across the growth plate of developing bovine ribs

2002 ◽  
Vol 361 (2) ◽  
pp. 231-241 ◽  
Author(s):  
Sujata G. PANDIT ◽  
Prasanthi GOVINDRAJ ◽  
Joachim SASSE ◽  
Peter J. NEAME ◽  
John R. HASSELL
Keyword(s):  
Growth Factor ◽  
Fibroblast Growth Factor ◽  
Growth Plate ◽  
Point Mutations ◽  
Growth Factor Receptor ◽  
Fibroblast Growth ◽  
Fgf Receptor ◽  
Hypertrophic Zone ◽  
The Matrix ◽  
Maximum Expression

Point mutations in the human fibroblast growth factor (FGF) receptor 3 gene (Fgfr3) produce a constitutively active receptor, which disrupts chondrocyte differentiation in the growth plate and results in skeletal dysplasias with severe shortening of the limbs. Alternative splicing of the Fgfr3 transcript gives rise to two isoforms, IIIc and IIIb, which vary in their specificity for FGF ligands. We examined the expression of these FGFR3 isoforms in the bovine fetal rib growth plate to determine whether levels of FGFR3 expression are zone-related. Transcripts for both Fgfr3 isoforms are expressed in rib growth plate, with maximum expression in the hypertrophic region and the least expression in the reserve zone. Fgfr3 IIIc is the predominant isoform in the growth plate. Western-blot analysis revealed the presence of full-length FGFR3 (135kDa) for both isoforms in the reserve zone, a major 98kDa fragment in all zones and smaller fragments primarily in the hypertrophic zone. Immunostaining localized FGFR3 to the pericellular region of reserve chondrocytes and to the extracellular matrix in the hypertrophic zone. These results suggest that the transmembrane form of FGFR3 increasingly undergoes proteolytic cleavage towards the hypertrophic zone to produce an extracellular-domain fragment of FGFR3, which is present in large amounts in the matrix of hypertrophic cells. These findings suggest a proteolytic regulatory mechanism for FGFR3, whereby Fgfr3 fragments could control availability of FGF for the intact receptor, and by which proteolysis could inactivate the receptor.

Development of a High Throughput Screening Assay for Inhibitors of Fibroblast Growth Factor-Receptor-Heparin Interactions

2001 ◽  
Vol 6 (3) ◽  
pp. 171-177 ◽  
Author(s):  
David Aviezer ◽  
Andrew P. Seddon ◽  
Mary Jo Wildey ◽  
Peter Böhlen ◽  
Avner Yayon
Keyword(s):  
Alkaline Phosphatase ◽  
Growth Factors ◽  
Growth Factor ◽  
Tumor Progression ◽  
Receptor Binding ◽  
High Throughput ◽  
High Throughput Screening ◽  
Growth Factor Receptor ◽  
Fibroblast Growth ◽  
Fgf Receptor

High throughput screening (HTS) of large compound libraries for inhibitors of growth factors raises the requirement for simple yet reliable assays. Fibroblast growth factors (FGFs) play a pivotal role in the multistep pathway of malignant transformation, tumor progression, metastasis, and angiogenesis. FGF-2 (basic FGF) requires a cooperative interaction with heparin or heparan sulfate proteoglycans in order to form functional growth factor-receptor complexes that are essential for receptor binding and activation. We have developed a simple screening system, devised to identify molecules that modulate heparin-FGF-receptor interactions. The system is composed of a heparin matrix, FGF-2, and a FGF receptor-1 protein engineered by genetically fusing the extracellular domain of FGF receptor-1 to alkaline phosphatase (FRAP). The screen is conducted using 96-well plates to which heparin has been covalently attached. FGF-2 is then bound to the plates through heparin-FGF interactions, followed by the addition of FRAP and compounds to be screened for modulation of heparin-FGF, receptor-heparin, and receptor-FGF interactions. The endpoint of the assay is measured enzymatically using the alkaline phosphatase (AP)-catalyzed formation of a chromogenic product, which is directly proportional to the amount of FRAP present on the plates as a heparin-FGF-FRAP ternary complex. Reduced AP values relative to control, as measured by spectrophotometry, indicate inhibition of the formation of an active FGF-receptor-heparin complex. The simple and versatile nature of the assay makes it an attractive HTS system. The screen has identified several potent inhibitors of FGF-2 receptor binding and activation. Furthermore, secondary screening of the HTS-recognized compounds identified several compounds that have the capacity to block growth factor-mediated tumor progression and angiogenesis in vivo.

Spatially restricted expression of set mRNA in developing rat kidney

1994 ◽  
Vol 266 (1) ◽  
pp. F155-F161
Author(s):  
E. G. Kim ◽  
M. E. Choi ◽  
B. J. Ballermann
Keyword(s):  
Rat Kidney ◽  
Cdna Probe ◽  
Protein Product ◽  
Open Reading Frames ◽  
Neonatal Rat ◽  
Ribonuclease Protection Assay ◽  
Cortical Region ◽  
Intracellular Protein ◽  
Translocation Event ◽  
Developing Rat

A somatic translocation event fusing the novel gene set to the putative oncogene can has been implicated in the development of acute nonlymphocytic leukemia in humans. In this study, full-length cDNAs highly homologous with human set were cloned from a rat neonatal kidney library. The expression pattern of set mRNA was then examined in developing rat kidney. Two groups of set cDNAs (alpha and beta) with different translation initiation sites and open reading frames of 867 and 831 bp, respectively, were found. The predicted protein products are 33,385 and 32,085 Da in size and contain approximately 30% acidic residues, over half of them clustered at the COOH terminal, thus forming a long acidic tail. No signal peptide or membrane-spanning domains were identified, suggesting an intracellular protein product. By ribonuclease protection assay, both alpha and beta variants of set were expressed in kidney. On Northern blots of total kidney RNA, 3.0- and 2.2-kb mRNAs hybridized with the labeled set cDNA probe. Expression of both transcripts was four- to eightfold greater in neonatal compared with adult rat kidney. When neonatal rat kidneys were examined for set mRNA expression by in situ hybridization with 35S-labeled riboprobe, expression was densely localized in the cortical region of morphogenesis over primitive nephron structures, including S-shaped bodies. Thus mRNA for Set, a putative intracellular protein involved in leukemogenesis, is expressed in kidney.(ABSTRACT TRUNCATED AT 250 WORDS)

Spatially restricted expression of fibroblast growth factor receptor-2 during Xenopus development

Development ◽  
1992 ◽  
Vol 116 (4) ◽  
pp. 1051-1058 ◽  
Author(s):  
R. Friesel ◽  
S.A. Brown
Keyword(s):  
Growth Factor ◽  
Fibroblast Growth Factor ◽  
Fibroblast Growth Factor Receptor ◽  
Sequence Similarity ◽  
Growth Factor Receptor ◽  
Otic Vesicle ◽  
Amino Acid Sequence Similarity ◽  
Fibroblast Growth ◽  
Fgf Receptor ◽  
Mesoderm Inducing Factors

The fibroblast growth factors (FGFs) play a role in Xenopus laevis embryonic development, particularly in the induction of ventral-type mesoderm. We have isolated a full-length cDNA from Xenopus that we have designated Xenopus fibroblast growth factor receptor-2 (XFGFR-2), with significant amino acid sequence similarity to the previously described bek gene (FGFR-2). We expressed the XFGFR-2 cDNA in COS1 cells and showed that it functions as an FGF receptor by binding radiolabeled FGF-2. RNA gel blot analysis demonstrates that unlike Xenopus fibroblast growth factor receptor-1 (XFGFR-1), XFGFR-2 mRNA expression begins during gastrulation and continues through early tadpole stages. Whole-mount in situ hybridization demonstrates that XFGFR-2 mRNA is localized to the anterior neural plate in early neurula stage embryos. Later in development, XFGFR-2 expression is found in the eye anlagen, midbrain-hindbrain boundary and the otic vesicle. In addition, XFGFR-2 transcripts are expressed in animal caps in a manner that is independent of mesoderm-inducing factors. These results indicate that XFGFR-2 may have a role in development that is distinct from that of XFGFR-1.

scholarly journals Role of fibroblast growth factor receptor signaling in kidney development

2011 ◽  
Vol 301 (2) ◽  
pp. F245-F251 ◽  
Author(s):  
Carlton M. Bates
Keyword(s):  
Growth Factor ◽  
Fibroblast Growth Factor ◽  
Kidney Development ◽  
Growth Factor Receptor ◽  
Conditional Knockout ◽  
Fibroblast Growth ◽  
Metanephric Mesenchyme ◽  
Fibroblast Growth Factor Receptors ◽  
Conditional Deletion ◽  
Developing Kidney

Fibroblast growth factor receptors (Fgfrs) consist of four signaling family members and one nonsignaling “decoy” receptor, Fgfr-like 1 (Fgfrl1), all of which are expressed in the developing kidney. Several studies have shown that exogenous fibroblast growth factors (Fgfs) affect growth and maturation of the metanephric mesenchyme (MM) and ureteric bud (UB) in cultured tissues. Transgenic and conditional knockout approaches in whole animals have shown that Fgfr1 and Fgfr2 (predominantly the IIIc isoform) in kidney mesenchyme are critical for early MM and UB formation. Conditional deletion of the ligand, Fgf8, in nephron precursors or global deletion of Fgfrl1 interrupts nephron formation. Fgfr2 (likely the IIIb isoform signaling downstream of Fgf7 and Fgf10) is critical for ureteric morphogenesis. Moreover, Fgfr2 appears to act independently of Frs2α (the major signaling adapter for Fgfrs) in regulating UB branching. Loss of Fgfr2 in the MM leads to many kidney and urinary tract anomalies, including vesicoureteral reflux. Thus Fgfr signaling is critical for patterning of virtually all renal lineages at early and later stages of development.

scholarly journals Fibroblast Growth Factor (FGF) Receptor Mutations: A Pathway to Understanding Multigenic Risk in Disease?

2013 ◽  
Vol 1 (3) ◽  
pp. 123-127
Author(s):  
Stuart J. Mires
Keyword(s):  
Growth Factor ◽  
Fibroblast Growth Factor ◽  
Disease Risk ◽  
Selection Process ◽  
Growth Factor Receptor ◽  
Paternal Age ◽  
Fibroblast Growth ◽  
Gain Of Function ◽  
Fgf Receptor ◽  
Paternal Age Effect

Fibroblast growth factor receptor (FGFR) gain-of-function mutations form the pathogenic basis of multiple congenital pathologies. A pioneering body of work over the past two decades has established that a unique mutation selection process within the testis likely underlies the paternal age effect characteristics of such diseases. This mechanism, analogous to positive selection of mutations promo­ting proliferation in tumorigenesis, sparked interest in mutation profiling of testicular and other cancers. The resulting discovery of FGFR gain-of-function mutations akin to those of congenital syndromes has enabled a novel hypothesis to be born: that mutations represent a spectrum of activation. As such, FGFR gain-of-function mutations could be pathogenic not solely in defined monogenic syndromes but within myriad disease processes with ‘low activation’ conferring increased disease risk. Do such mutations contribute to multigenic risk in multiple pathologies? This review evaluates this hypothesis, alluding to the plausible clinical implications that ensue.

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