The vertebral column derives from somites generated by segmentation of presomitic mesoderm (PSM). Somitogenesis involves a molecular oscillator, the segmentation clock, controlling periodic Notch signaling in the PSM. Here, we establish a novel link between Wnt/beta-catenin signaling and the segmentation clock. Axin2, a negative regulator of the Wnt pathway, is directly controlled by Wnt/beta-catenin and shows oscillating expression in the PSM, even when Notch signaling is impaired, alternating with Lfng expression. Moreover, Wnt3a is required for oscillating Notch signaling activity in the PSM. We propose that the segmentation clock is established by Wnt/beta-catenin signaling via a negative-feedback mechanism and that Wnt3a controls the segmentation process in vertebrates.

Generation of mutant mice and genotypingCytokeratin 19 (K19) promoter-driven Cre mice (K19-Cre) were previously generated by a knock-in of the Cre recombinase gene into the ATG translation initiation codon of exon1 of K19 (Harada et al., 1999). The β-catenin floxed (flox) allele and the β-catenin floxed deleted (floxdel) allele were previously described (Brault et al., 2001). K19-Cre mice were mated with β-catenin floxdel mice and the offspring, which inherited both alleles, were crossed with homozygous β-catenin flox mice; a quarter of the offspring was positive for K19-Cre, together with one flox and one floxdel allele. Littermates, which inherited the floxed and floxdel β-catenin alleles but did not carry the K19-Cre allele served as heterozygous controls. Mutant animals were bred on a mixed 129SvϫC57Bl/6 background. PCR genotyping was performed as described previously (Lickert et al., 2002). Microarray experimentsMicroarray experiments have been submitted to GEO in a MIAME compliant format (Minimum Information About a Microarray Experiment) (Brazma et al., 2001). The accession number is GSE2519.

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During mammalian development, the Cdx1 homeobox gene exhibits an early period of expression when the embryonic body axis is established, and a later period where expression is restricted to the embryonic intestinal endoderm. Cdx1 expression is maintained throughout adulthood in the proliferative cell compartment of the continuously renewed intestinal epithelium, the crypts. In this study, we provide evidence in vitro and in vivo that Cdx1 is a direct transcriptional target of the Wnt/(beta)-catenin signaling pathway. Upon Wnt stimulation, expression of Cdx1 can be induced in mouse embryonic stem (ES) cells as well as in undifferentiated rat embryonic endoderm. Tcf4-deficient mouse embryos show abrogation of Cdx1 protein in the small intestinal epithelium, making Tcf4 the likely candidate to transduce Wnt signal in this part of gut. The promoter region of the Cdx1 gene contains several Tcf-binding motifs, and these bind Tcf/Lef1/(beta)-catenin complexes and mediate (beta)-catenin-dependent transactivation. The transcriptional regulation of the homeobox gene Cdx1 in the intestinal epithelium by Wnt/(beta)-catenin signaling underlines the importance of this signaling pathway in mammalian endoderm development.

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