Periodic Notch inhibition by Lunatic Fringe underlies the chick segmentation clock

Abstract

The segmented aspect of the vertebrate body plan first arises through the sequential formation of somites. The periodicity of somitogenesis is thought to be regulated by a molecular oscillator, the segmentation clock, which functions in presomitic mesoderm cells. This oscillator controls the periodic expression of 'cyclic genes', which are all related to the Notch pathway. The mechanism underlying this oscillator is not understood. Here we show that the protein product of the cyclic gene lunatic fringe (Lfng), which encodes a glycosyltransferase that can modify Notch activity, oscillates in the chick presomitic mesoderm. Overexpressing Lfng in the paraxial mesoderm abolishes the expression of cyclic genes including endogenous Lfng and leads to defects in segmentation. This effect on cyclic genes phenocopies inhibition of Notch signalling in the presomitic mesoderm. We therefore propose that Lfng establishes a negative feedback loop that implements periodic inhibition of Notch, which in turn controls the rhythmic expression of cyclic genes in the chick presomitic mesoderm. This feedback loop provides a molecular basis for the oscillator underlying the avian segmentation clock.

Lunatic fringe causes expansion and increased neurogenesis of trunk neural tube and neural crest populations

“…In embryos infected with lunatic fringe retrovirus, there was an upregulation of Delta-1-expressing cells in the pre-somitic mesoderm, as shown before (Dale et al, 2003). There was also an increase in the intermediate neural plate that will give rise to neural crest precursors (arrowheads in Fig.…”

“…Lunatic fringe is expressed in an oscillatory pattern in the presomitic mesoderm (McGrew et al, 1998) and mutations in this gene result in severe somite segmentation defects caused by periodic inhibition of Notch (Eph Nomenclature Committee, 1997; Evrard et al, 1998;Dale et al, 2003). Both lunatic fringe and radical fringe are expressed highly in the developing nervous system of vertebrate embryos (Johnston et al, 1997), although little is known about their function therein.…”

Sequence and embryonic expression of three zebrafish fringe genes: lunatic fringe, radical fringe, and manic fringe

“…By contrast, zebrafish lfng is only expressed in the rostral parts of formed somites and in the most anterior extremity of the PSM where the new somites are about to form (Forsberg et al, 1998;McGrew et al, 1998;Aulehla and Johnson, 1999;Prince et al, 2001;Leve et al, 2001;Dale et al, 2003; data not shown). It is possible that the described lfng is not the ortholog of mouse/chick Lfng and that some other fringe is cyclically expressed in the zebrafish PSM.…”

“…Fringe-modulated deployment of Notch signaling has been shown to be critical for formation of developmental boundaries in Drosophila wing, Drosophila eye, Drosophila leg, chicken limb, vertebrate somites, and chicken zona limitans intrathalamica (zli) and may have a similar role in other tissues such as the hindbrain, although the detailed mechanisms Wu et al, 1996;c Appel et al, 2003;d Prince et al, 2001; e Leve et al, 2001;f Sakamoto et al, 1997;g Laufer et al, 1997;h Johnston et al, 1997;i Cohen et al, 1997;j Ishii et al, 2000;k Mikami et al, 2001;l Zeltser et al, 2001;m Cole et al, 2000;n Morsli et al, 1998;o McGrew et al, 1998;p Aulehla and Johnson, 1999;q Thelu et al, 2002;r Pouyet and Mitsiadis, 2000;s Harada et al, 1999;t Mustonen et al, 2002;u Chen and Chuong, 2000;v Favier et al, 2000;w Christen and Slack, 1998;x Cadinouche et al, 1999;y Rodriguez-Esteban et al, 1997;z Singh et al, 2000. may vary (reviewed in Irvine and Rauskolb, 2001). Fringe is also important for some other Notchdependent processes; in chick and mouse, in particular, it plays an essential part in the "segmentation clock"-the oscillation of gene expression in the presomitic mesoderm during somitogenesis (Dale et al, 2003).…”

WNT signaling, in synergy with T/TBX6, controls Notch signaling by regulating Dll1 expression in the presomitic mesoderm of mouse embryos

“…Furthermore, mutations in some Notch pathway components, which lead to defects in somitogenesis, also affect the expression of cyclic genes (del Barco Barrantes et al 1999;Jiang et al 2000;Jouve et al 2000;Dunwoodie et al 2002), indicating that Notch signaling is essential for generating cyclic gene expression. Cyclic Lfng gene expression was shown in chick and mouse embryos to be essential for Lfng function (Dale et al 2003;Serth et al 2003). Disruption of WNT/ ␤-catenin signaling also affects somitogenesis and cyclic expression of Notch pathway components, whereas cyclic Axin2 expression is maintained when Notch signaling is impaired (Aulehla et al 2003;Aulehla and Herrmann 2004), suggesting that WNT acts upstream of Notch in the segmentation clock.…”