Mouse anti-Human RFNG monoclonal antibody, clone 7D8

Drosophila fringe and its homologues in vertebrates code for glycosyltransferases that modify Notch, altering the sensitivity of this receptor protein to its ligands Delta and Serrate and, thereby, playing an essential part in the demarcation of tissue boundaries. We describe the isolation and characterization of three zebrafish (Danio rerio) fringe homologues: lunatic fringe (lfng), radical fringe (rfng), and manic iFringe (mfng). In addition to the sites previously described (Prince et al. [2001] Mech. Dev. 105:175-180; Leve et al. [2001] Dev. Genes Evol. 211:493-500), Ifng is also expressed in the sensory patches of the inner ear. The newly described rfng is expressed in adaxial cells, tectum, rhombomere boundaries, and formed somites, but the expression of mfng is only detectable by reverse transcription-polymerase chain reaction and not by whole-mount in situ hybridization (WISH) during early embryonic development; later, it is expressed in the sensory patches of the ear. In mib mutants, where Notch signaling is defective and rhombomere boundaries fail to form, the rfng expression in hindbrain is almost completely lost. None of the three zebrafish fringe genes is detectably expressed in the posterior presomitic mesoderm, suggesting that, in contrast with chick and mouse, the somitogenesis oscillator in this tissue in the zebrafish does not depend on Fringe activity. (C) 2004 Wiley-Liss, Inc.

Alagille syndrome (AGS) is a heterogeneous developmental disorder associated with bile duct paucity and various organ anomalies. The syndrome is caused by mutations in JAG1, which encodes a ligand in the Notch signaling pathway, in the majority of cases and mutations in the NOTCH2 receptor gene in less than 1% of patients. Although a wide array of JAG] mutations have been identified in the AGS population, these mutational variants have not accounted for the wide phenotypic variability observed in patients with this syndrome. The Fringe genes encode glycosyltransferases, which modify Notch and alter ligand-receptor affinity. In this study, we analyzed double heterozygous mouse models to examine the Fringe genes as potential modifiers of the Notch-mediated hepatic phenotype observed in AGS. We generated mice that were haploinsufficient for both Jag1 and one of three paralogous Fringe genes: Lunatic (Lfng), Radical (Rfng), and Manic (Mfng). Adult Jag1(+/-)Lfng(+/-) and Jag1(+/-)Rfng(+/-) mouse livers exhibited widespread bile duct proliferation beginning at 5 weeks of age and persisting up to I year. The Jag1(+/-)Mfng(+/-) livers showed a subtle, yet significant increase in bile duct numbers and bile duct to portal tract ratios. These abnormalities were not observed in the newborn period. Despite the portal tract expansion by bile ducts, fibrosis was not increased and epithelial to mesenchymal transition was not shown in the affected portal tracts. Conclusion: Mice heterozygous for mutations in Jag] and the Fringe genes display striking bile duct proliferation, which is not apparent at birth. These findings suggest that the Fringe genes may regulate postnatal bile duct growth and remodeling, and serve as candidate modifiers of the hepatic phenotype in AGS. (HEPATOLOGY 2008;48:.1989-1997.)