1. Laboratoire de génétique et de physiologie du développement, Institut de biologie du développement de Marseille, CNRS-INSERM-Université de la méditerranée-AP de Marseille, Campus de Luminy, Case 907,13288 Marseille Cedex 09, France
2. These authors contributed equally to this work
3. Present addresses: Stowers Institute for Medical Research, 1000 East 50th Street, Kansas City, Missouri 64110, USA (J.K.D., M.M., M.-L.D., P.M. and O.P.); Department of Gene Expression and Development, Roslin Institute, Roslin EH25 9PS, UK (M.McG.)

Correspondence to: O. Pourquie² Correspondence and requests for materials should be addressed to O.P. (e-mail: Email: olp@stowers-institute.org).

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^{1, 2, 3, 4, 5, 6, 7}. 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.