The anterior-posterior axis of the mouse embryo is defined before formation of the primitive streak, and axis specification and subsequent anterior development involves signaling from both embryonic ectoderm and visceral endoderm. Τhe Wnt signaling pathway is essential for various developmental processes, but a role in anterior-posterior axis formation in the mouse has not been previously established. β-Catenin is a central player in the Wnt pathway and in cadherin-mediated cell adhesion. We generated β-catenin–deficient mouse embryos and observed a defect in anterior-posterior axis formation at embryonic day 5.5, as visualized by the absence of Hex and Hesx1 and the mislocation of cerberus-like and Lim1 expression. Subsequently, no mesoderm and head structures are generated. Intercellular adhesion is maintained since plakoglobin substitutes for β-catenin. Our data demonstrate that β-catenin function is essential in anterior-posterior axis formation in the mouse, and experiments with chimeric embryos show that this function is required in the embryonic ectoderm.

The epithelial–mesenchymal transition is essential in both embryonic development and the progression of carcinomas. Wnt signaling and cadherin-mediated adhesion have been implicated in both processes; clarifying their role will depend on linking them to rearrangements of cellular structure and behavior. β-Catenin is an essential molecule both in cadherin-mediated cell adhesion and in canonical Wnt signaling. Numerous experiments have shown that the loss of cadherin-mediated cell adhesion can promote β-catenin release and signaling; this is accomplished by proteases, protein kinases and other molecules. Cadherin loss can also signal to several other regulatory pathways. Additionally, many target genes of Wnt signaling influence cadherin adhesion. The most conspicuous of these Wnt target genes encode the transcription factors Twist and Slug, which directly inhibit the E-cadherin gene promoter. Other Wnt/β-catenin target genes encode metalloproteases or the cell adhesion molecule L1, which favor the degradation of E-cadherin. These factors provide a mechanism whereby cadherin loss and increased Wnt signaling induce epithelial–mesenchymal transition in both carcinomas and development.

Wnt signaling is one of a handful of powerful signaling pathways that play crucial roles in the animal life by controlling the genetic programs of embryonic development and adult homeostasis. When disrupted, these signaling pathways cause developmental defects, or diseases, among them cancer. The gateway of the canonical Wnt pathway, which contains >100 genes, is an essential molecule called β-catenin (Armadillo in Drosophila). Conditional loss- and gain-of-function mutations of β-catenin in mice provided powerful tools for the functional analysis of canonical Wnt signaling in many tissues and organs. Such studies revealed roles of Wnt signaling that were previously not accessible to genetic analysis due to the early embryonic lethality of conventional β-catenin knockout mice, as well as the redundancy of Wnt ligands, receptors, and transcription factors. Analysis of conditional β-catenin loss- and gain-of-function mutant mice demonstrated that canonical Wnt signals control progenitor cell expansion and lineage decisions both in the early embryo and in many organs. Canonical Wnt signaling also plays important roles in the maintenance of various embryonic or adult stem cells, and as recent findings demonstrated, in cancer stem cell types. This has opened new opportunities to model numerous human diseases, which have been associated with deregulated Wnt signaling. Our review summarizes what has been learned from genetic studies of the Wnt pathway by the analysis of conditional β-catenin loss- and gain-of-function mice.

Heart formation requires the coordinated recruitment of multiple cardiac progenitor cell populations derived from both the first and second heart fields. In this study, we have ablated the Bmp receptor 1a and the Wnt effector β-catenin in the developing heart of mice by using MesP1-cre, which acts in early mesoderm progenitors that contribute to both first and second heart fields. Remarkably, the entire cardiac crescent and later the primitive ventricle were absent in MesP1-cre ; BmpR1a ^lox/lox mutants. Although myocardial progenitor markers such as Nkx2-5 and Isl1 and the differentiation marker MLC2a were detected in the small, remaining cardiac field in these mutants, the first heart field markers, eHand and Tbx-5 , were not expressed. We conclude from these results that Bmp receptor signaling is crucial for the specification of the first heart field. In MesP1-cre; β -catenin ^lox/lox mutants, cardiac crescent formation, as well as first heart field markers, were not affected, although cardiac looping and right ventricle formation were blocked. Expression of Isl1 and Bmp4 in second heart field progenitors was strongly reduced. In contrast, in a gain-of-function mutation of β-catenin using MesP1-cre, we revealed an expansion of Isl1 and Bmp4 expressing cells, although the heart tube was not formed. We conclude from these results that Wnt/β-catenin signaling regulates second heart-field development, and that a precise amount and/or timing of Wnt/β-catenin signaling is required for proper heart tube formation and cardiac looping.

Wound healing of the skin is a crucial regenerative process in adult mammals. We examined wound healing in conditional mutant mice, in which the c-Met gene that encodes the receptor of hepatocyte growth factor/scatter factor was mutated in the epidermis by cre recombinase. c-Met–deficient keratinocytes were unable to contribute to the reepithelialization of skin wounds. In conditional c-Met mutant mice, wound closure was slightly attenuated, but occurred exclusively by a few (5%) keratinocytes that had escaped recombination. This demonstrates that the wound process selected and amplified residual cells that express a functional c-Met receptor. We also cultured primary keratinocytes from the skin of conditional c-Met mutant mice and examined them in scratch wound assays. Again, closure of scratch wounds occurred by the few remaining c-Met–positive cells. Our data show that c-Met signaling not only controls cell growth and migration during embryogenesis but is also essential for the generation of the hyperproliferative epithelium in skin wounds, and thus for a fundamental regenerative process in the adult.

β-Catenin controls both cadherin-mediated cell adhesion and activation of Wnt target genes. We demonstrate here that the β-catenin-binding protein BCL9-2, a homolog of the human proto-oncogene product BCL9, induces epithelial-mesenchymal transitions of nontransformed cells and increases β-catenin-dependent transcription. RNA interference of BCL9-2 in carcinoma cells induces an epithelial phenotype and translocates β-catenin from the nucleus to the cell membrane. The switch between β-catenin's adhesive and transcriptional functions is modulated by phosphorylation of Tyr 142 of β-catenin, which favors BCL9-2 binding and precludes interaction with α-catenin. During zebrafish embryogenesis, BCL9-2 acts in the Wnt8-signaling pathway and regulates mesoderm patterning.