Fringe differentially modulates Jagged1 and Delta1 signalling through Notch1 and Notch2

Abstract

Proteins encoded by the fringe family of genes are required to modulate Notch signalling in a wide range of developmental contexts. Using a cell co-culture assay, we find that mammalian Lunatic fringe (Lfng) inhibits Jagged1-mediated signalling and potentiates Delta1-mediated signalling through Notch1. Lfng localizes to the Golgi, and Lfng-dependent modulation of Notch signalling requires both expression of Lfng in the Notch-responsive cell and the Notch extracellular domain. Lfng does not prevent binding of soluble Jagged1 or Delta1 to Notch1-expressing cells. Lfng potentiates both Jagged1- and Delta1-mediated signalling via Notch2, in contrast to its actions with Notch1. Our data suggest that Fringe-dependent differential modulation of the interaction of Delta/Serrate/Lag2 (DSL) ligands with their Notch receptors is likely to have a significant role in the combinatorial repertoire of Notch signalling in mammals.

Physiology and pathology of notch signalling system

“…This enzyme may up-or downregulate the ability of several ligands to activate Notch receptors (Hicks et al, 2000). The modulatory function of Notch signalling performed by Fringe proteins, initially identified in Drosophila, has also been confirmed in mammals (Brukner et al, 2000;Moloney et al, 2000).…”

Molecular Genetics of Vestibular Organ Development

“…L-fng is an ortholog of the Drosophila fringe gene that acts in the Notch signaling pathway to establish boundaries during the development of both flies and vertebrates (Laufer et al 1997;Panin et al 1997;Evrard et al 1998;Papayannopoulos et al 1998;Zhang and Gridley 1998). Recent data show that Fringe mediates its effect by forming complexes with Notch receptors and modulating their ligand preferences (Hicks et al 2000;Ju et al 2000). In the inner ear, L-fng is expressed in an anterolateral domain of the otic cup that later expands medially (Morsli et al 1998; Fig.…”

Notch and Wnt signaling in T-lymphocyte development and acute lymphoblastic leukemia

“…46 Furthermore, the interaction of Notch with the different ligands can be modulated by Fringe proteins. 17 Overexpression in the thymus of Lunatic Fringe, which is thought to inhibit Notch activation by Jagged and facilitate interaction with Delta, 47 blocked T-cell commitment. 48 The downstream mechanisms by which a Notch signal is translated into a T-cell program are still largely unclear.…”