Cdx, Hox and the genetics of axial extension in the mouse

The three mouse Cdx genes, Cdx1, Cdx2 and Cdx4, encode Hox-related transcription factors that play overlapping functions in patterning the embryo and in ensuring the completion of its posterior axial elongation, with Cdx2 as the major contributor. We show that Cdx and Hox genes are crucial players in embryonic axial extension. Cdx mutants exhibit a caudal truncation that can be rescued by a gain of posterior expression of some of the central Hox genes. The precocious arrest of axial growth in Cdx mutants can also be cured by a posterior activation of the Wnt effector Lef1, revealing a positive feedback of Cdx on Wnt signaling. The last paralogous group of Hox genes, Hox13, was shown to negatively interfere with this process, antagonizing more anterior Hox and Cdx genes, thus counteracting their growth-stimulating Wnt signaling in the posterior growth zone. The effect of inactivating all three Cdx genes is described for the first time. Embryos developing in the absence of Cdx genes only form head structures. In Cdx null embryos, no tissue is generated caudal to the occipital region. The progenitors residing in the posterior growth zone of these embryos seem to be eliminated at E8.5, as can be judged by the lack of tissue generation after this stage and the absence of expression of posterior marker genes. Expression of anterior Hox genes is initiated normally in early Cdx null mutant embryos, but it fades away posteriorly in the exhausted growth zone by E8.5. This also shows that the initiation of the earliest Hox gene expression is not dependent on Cdx genes. The function of Cdx genes in trunk and tail (post-head) development appears to have been conserved during evolution. Cdx activity, canonical Wnt signaling and correct timing of Hox gene expression, are required for morphogenesis of the posterior neurepithelium and digestive tract, in addition to their obligatory role in the regulation of vertebral axis extension. Cdx2+/-Cdx4-/- and Wnt3a hypomorph embryos and embryos precociously expressing Hox13 genes suffer from anorectal malformations and aberrant neurepithelial development reminiscent of a human syndrome called “Caudal Regression”. We demonstrate that, although these tissue deficiencies are observed late in development, Cdx and Wnt impact on tissue progenitors at the time they still reside in the posterior growth zone several days earlier. Cdx and Hox genes regulate Wnt signaling, possibly by affecting the expression of Wnt pathway components Nkd1 and Frzb.