Alternative titles; symbols
HGNC Approved Gene Symbol: RFNG
Cytogenetic location: 17q25.3 Genomic coordinates (GRCh38): 17:82,047,902-82,051,811 (from NCBI)
The Drosophila melanogaster 'fringe' gene is a secreted signaling protein that participates in the formation of boundaries between groups of cells during development. The fringe protein acts by modulating the activation of the Notch (for example, see 190198) signal transduction pathway at the dorsal-ventral boundary of the Drosophila wing imaginal disc. Johnston et al. (1997) identified 3 human expressed sequence tags (ESTs) with homology to fringe and used them to clone the corresponding genes from mouse. They named the genes radical fringe (Rfng), lunatic fringe (Lfng; 602576), and manic fringe (Mfng; 602577). The predicted 332-amino acid mouse Rfng protein has a putative signal peptide. When misexpressed in the Drosophila wing disc, Rfng mimics some of the activities of Drosophila fringe. Expression studies of the fringe homologs in mouse embryos by in situ hybridization suggested that all 3 homologs participate in the Notch signaling pathway in determining boundaries during segmentation and cell fates during neurogenesis.
Moran et al. (1999) characterized the genomic loci of the fringe gene family members, revealing a conserved genomic organization of 8 exons. Comparative analysis of mammalian fringe genomic organization suggested that the first exon is evolutionarily labile and that the fringe genes have a genomic structure distinct from those of previously characterized glycosyltransferases.
By somatic cell hybridization, Moran et al. (1999) mapped the RFNG gene to human chromosome 17q25. By interspecific backcross analysis, they mapped the homologous gene in the mouse to chromosome 11.
Fringe proteins can positively and negatively modulate the ability of Notch ligands to activate the Notch receptor. Moloney et al. (2000) established the biochemical mechanism of Fringe action. Drosophila and mammalian Fringe proteins possess a fucose-specific beta-1,3 N-acetylglucosaminyltransferase activity that initiates elongation of O-linked fucose residues attached to epidermal growth factor (EGF; 131530)-like sequence repeats of Notch. They obtained biologic evidence that Fringe-dependent elongation of O-linked fucose on Notch modulates Notch signaling by using coculture assays in mammalian cells and by expression of an enzymatically inactive Fringe mutant in Drosophila. Bruckner et al. (2000) showed that Fringe acts in the Golgi as a glycosyltransferase enzyme that modifies the EGF modules of Notch and alters the ability of Notch to bind its ligand Delta (602768). The authors demonstrated that Fringe catalyzes the addition of N-acetylglucosamine to fucose, which is consistent with a role in the elongation of O-linked fucose O-glycosylation that is associated with EGF repeats.
Vertebrate limb outgrowth requires a structure called the apical ectodermal ridge (AER), formation of which relies on the previous establishment of the dorsoventral limb axis. The AER of the vertebrate limb bud lies at the junction of the dorsal and ventral ectoderm and directs patterning of the growing limb outgrowth. Rfng is expressed in the dorsal ectoderm before the ridge appears, and is repressed by Engrailed-1 (131290), which is expressed in the ventral ectoderm. Rodriguez-Esteban et al. (1997) found that misexpression of these genes results in a ridge being formed wherever there is a boundary between cells expressing and not expressing Rfng. Thus, as in Drosophila, Rfng positions the ridge at the dorsoventral limb boundary. The results of Laufer et al. (1997) supported the hypothesis that the AER forms at the juxtaposition of Rfng-expressing and nonexpressing cells, and furthermore dissociate the molecular control of AER formation from that of dorsoventral tissue specification. Laufer et al. (1997) also found that Rfng expression in chick limb dorsal ectoderm is established in part through repression by Engrailed-1 in the ventral ectoderm.
Bruckner, K., Perez, L., Clausen, H., Cohen, S. Glycosyltransferase activity of Fringe modulates Notch-Delta interactions. Nature 406: 411-415, 2000. Note: Erratum: Nature 407: 654 only, 2000. [PubMed: 10935637] [Full Text: https://doi.org/10.1038/35019075]
Johnston, S. H., Rauskolb, C., Wilson, R., Prabhakaran, B., Irvine, K. D., Vogt, T. F. A family of mammalian Fringe genes implicated in boundary determination and the Notch pathway. Development 124: 2245-2254, 1997. [PubMed: 9187150] [Full Text: https://doi.org/10.1242/dev.124.11.2245]
Laufer, E., Dahn, R., Orozco, O. E., Yeo, C.-Y., Pisenti, J., Henrique, D., Abbott, U. K., Fallon, J. F., Tabin, C. Expression of Radical fringe in limb-bud ectoderm regulates apical ectodermal ridge formation. Nature 386: 366-373, 1997. Note: Erratum: Nature 388: 400 only, 1997. [PubMed: 9121552] [Full Text: https://doi.org/10.1038/386366a0]
Moloney, D. J., Panin, V. M., Johnston, S. H., Chen, J., Shao, L., Wilson, R., Wang, Y., Stanley, P., Irvine, K. D., Haltiwanger, R. S., Vogt, T. F. Fringe is a glycosyltransferase that modifies Notch. Nature 406: 369-375, 2000. [PubMed: 10935626] [Full Text: https://doi.org/10.1038/35019000]
Moran, J. L., Johnston, S. H., Rauskolb, C., Bhalerao, J., Bowcock, A. M., Vogt, T. F. Genomic structure, mapping, and expression analysis of the mammalian lunatic, manic, and radical fringe genes. Mammalian Genome 10: 535-541, 1999. [PubMed: 10341080] [Full Text: https://doi.org/10.1007/s003359901039]
Rodriguez-Esteban, C., Schwabe, J. W. R., De La Pena, J., Foys, B., Eshelman, B., Izpisua Belmonte, J. C. Radical fringe positions the apical ectodermal ridge at the dorsoventral boundary of the vertebrate limb. Nature 386: 360-366, 1997. Note: Erratum: Nature 388: 906 only, 1997. [PubMed: 9121551] [Full Text: https://doi.org/10.1038/386360a0]