A loss-of-function mutation in the mouse delta-like3 (Dll3)

Notch signalling is an evolutionarily conserved mechanism used by metazoans to control the specification of cell fates through local interactions between cells (Artavanis-Tsakonas et al., 1999). As ligand and receptor are membrane associated, signalling is triggered by direct interaction of adjacent cells. In general, the Notch receptor is widely distributed within a cell population, while the ligand is restricted to a subset of cells (Fleming et al., 1990; Heitzler and Simpson, 1991; Vassin et al., 1987; Wharton et al., 1985). While several proteins participate in transmitting and regulating Notch signalling, a group of elements are defined as the core of this signalling pathway: in Drosophila, Delta and Serrate are Notch ligands, the transcription factor Suppressor of Hairless [Su(H)] is the major downstream effector (Bailey and Posakony, 1995; Lecourtois and Schweisguth, 1995), and genes of the Enhancer of Split [E(Spl)] locus (also transcription factors) are the primary targets of the pathway (Egan et al., 1998; Greenwald, 1998). Mammalian homologues have been identified for each of these core components and include Notch1, Notch2, Notch3 and Notch4 (Lardelli et al., 1994; Uyttendaele et al., 1996; Weinmaster et al., 1991; Weinmaster et al., 1992); Delta-like1 (Dll1), Dll3 and Dll4 (Bettenhausen et al., 1995; Dunwoodie et al., 1997; Shutter et al., 2000); Serrate homologues Jag1 and Jag2 (Lindsell et al., 1995; Shawber et al., 1996); Su(H) homologue RBPjK (Furukawa et al., 1992; Schweisguth and Posakony, 1992) and Hairy and Enhancer of Split homologues Hes1, Hes5 (Sasai et al., 1992; Takebayashi et al., 1995), Hey1 and Hey2 (also known as HRT/Hesr) (Kokubo et al., 1999; Leimeister et al., 1999; Nakagawa et al., 1999). The Notch signalling pathway is deployed in three types of processes: lateral inhibition, lineage decisions and boundary formation (Bray, 1998). In vertebrates, somite segmentation relies on boundary formation in rostral presomitic mesoderm, coincident with expression of genes associated with Notch signalling (del Barco Barrantes et al., 1999). Accordingly, boundary formation with respect to somitogenesis commands 1795 Development 129, 1795-1806 (2002) Printed in Great Britain © The Company of Biologists Limited 2002 DEV14507