Biomedical subjects

O Segev

Publications and source records attributed to O Segev.

6 recordsLinked to original sources

PubMed2000

Restrained chondrocyte proliferation and maturation with abnormal growth plate vascularization and ossification in human FGFR-3(G380R) transgenic mice.

Achondroplasia, the most common genetic form of human dwarfism, results from a point mutation (G380R) in the gene for fibroblast growth factor receptor 3 (FGFR-3). Heterozygotes for the mutation share disproportionate, proximal shortening of the limbs, mid-face hypoplasia and relative macrocephaly due to a failure in endochondral ossification. Here we have generated transgenic mice expressing the human mutant FGFR-3 under the transcriptional control of the mouse gene. Mice that are hemizygous for the mutant human gene display disproportionate dwarfism with skeletal phenotypes remarkably similar to those of human achondroplasia. Mice that are homozygous for the transgene suffer from a profound delay in skeletal development and die at birth, similar in that respect to humans homozygous for the achondroplasia mutant gene. Microscopic analysis of long bones demonstrates growth plate morphology compatible with that of human achondroplasia cases, sharing endochondral growth inhibition with restrained chondrocyte proliferation and maturation, penetration of ossification tufts and aberrant vascularization.

Animals↗

PubMed2000

The transmembrane mutation G380R in fibroblast growth factor receptor 3 uncouples ligand-mediated receptor activation from down-regulation.

A point mutation, Gly380Arg, in the transmembrane domain of fibroblast growth factor receptor 3 (FGFR3) leads to achondroplasia, the most common form of genetic dwarfism in humans. This substitution was suggested to enhance mutant receptor dimerization, leading to constitutive, ligand-independent activation. We found that dimerization and activation of the G380R mutant receptor are predominantly ligand dependent. However, using both transient and stable transfections, we found significant overexpression only of the mutant receptor protein. Metabolic pulse-chase experiments, cell surface labeling, and kinetics of uptake of radiolabeled ligand demonstrated a selective delay in the down-regulation of the mutant receptor. Moreover, this receptor was now resistant to ligand-mediated internalization, even at saturating ligand concentrations. Finally, transgenic mice expressing the human G380R mutant receptor under the mouse receptor transcriptional control demonstrated a markedly expanded area of FGFR3 immunoreactivity within their epiphyseal growth plates, compatible with an in vivo defect in receptor down-regulation. We propose that the achondroplasia mutation G380R uncouples ligand-mediated receptor activation from down-regulation at a site where the levels and kinetics of FGFR3 signals are crucial for chondrocyte maturation and bone formation.

Amino Acid Substitution↗

PubMed1994

Conserved cis-elements bind a protein complex that regulates Drosophila ras2/rop bidirectional expression.

The Drosophila ras2 promoter region exhibits bidirectional activity, as has been demonstrated for the human c-Ha-ras1 and the mouse c-Ki-ras. Here we address a unique case of ras regulation, as Drosophila ras2 provides the only example to date in which the flanking gene (rop) and its product have been isolated. A linking mechanism of control suggests a mutual interaction between the two gene products. Our studies indicate that the Drosophila ras2 promoter region shares with the human c-Ha-ras1 promoter a CACCC box and an AP-1-like sequence. A 14 bp promoter fragment which holds a CACCC element is demonstrated to interact with a specific transcription factor (factor B). This CACCC promoter element represents a stretch of imperfect palindrome. We present evidence that this factor can form a complex with another specific DNA-binding protein (factor A). The binding sites (A + B) for these protein factors are essential for 95% expression of both genes flanking the promoter (ras2 and rop). Region A consists of four overlapping consensus sequences: a TATA-like element, a DSE-like motif (the core sequence of the serum response element), a DRE octamer, which has been shown to play a role in cell proliferation, and a 5 bp direct repeat representing the GATA consensus sequence. Factor A has a very weak affinity to the full promoter region, but when complexed with factor B binding efficiency is enhanced. We also show that alterations of DNA-protein binding specificities can be achieved by supplementing the growth media with different sera.

Animals↗

PubMed1989

Maternal and embryonic transcripts of Drosophila proto-oncogenes are expressed in Schneider 2 culture cells but not in l(2)gl transformed neuroblasts.

The transcription patterns of Drosophila melanogaster src, abl and two ras homologs were analyzed in normal Drosophila tissue, in neuroblasts derived from tumorous larval brain of the mutant lethal(2)giant larvae [l(2)gl] and in Schneider 2 tissue culture cells. Our results show that, in addition to constitutive transcripts, the src, abl, ras1 and ras3 genes express a set of maternal/embryonic-specific transcripts. By using these transcripts as differentiation markers we show that, in spite of their embryonic-like, undifferentiated phenotype, the l(2)gl transformed neuroblasts are authentic larval cells. Using the same criterion the Schneider 2 tissue culture cells show the characteristics of embryonic cells.

Animals↗

PubMed1985

Expression of ras cellular oncogenes during development of Drosophila melanogaster.

The transcription patterns of three v-Ha-ras-related cellular oncogenes in Drosophila melanogaster were studied. Each gene coded for at least two distinct transcripts. The larger transcript of each gene was expressed at a similar abundance during the entire life cycle of fruit flies, whereas the shorter transcripts were much more abundant in embryonic stages than at later stages.

Animals↗

PubMed1984

Expression of the src and abl cellular oncogenes during development of Drosophila melanogaster.

Transcription of the Drosophila homologs of the abl and src cellular oncogenes, termed Dash and Dsrc , respectively, was studied. Despite the fact that Dash and Dsrc share sequence homology, they have distinct patterns of transcription during development. The Dash transcript, 6.2 kilobases long, is found in maternal RNA stored in unfertilized eggs and in embryos up to 4 h after egg laying. In contrast, Dsrc transcripts are 3.2, 4.8, and 5.2 kilobases long. They are detected in eggs and embryos and to a lesser extent in larvae and adult flies. The relative amount of each of the three Dsrc transcripts changes during the different stages of development.

Animals↗