Wnt signaling in stem and cancer stem cells.

The functional versatility of Wnt/ß-catenin signaling can be seen by its ability to act in stem cells of the embryo and of the adult as well as in cancer stem cells. During embryogenesis, stem cells demonstrate a requirement for ß-catenin in mediating the response to Wnt signaling for their maintenance and transition from a pluripotent state. In adult stem cells, Wnt signaling functions at various hierarchical levels to contribute to specification of different tissues. This has raised the possibility that the tightly regulated self-renewal mediated by Wnt signaling in stem and progenitor cells is subverted in cancer cells to allow malignant progression. Intensive work is currently being performed to resolve how intrinsic and extrinsic factors that regulate Wnt/ß-catenin signaling coordinate the stem and cancer stem cell states.

Wnt/ß-catenin and Bmp signals control distinct sets of transcription factors in cardiac progenitor cells.

Progenitor cells of the first and second heart fields depend on cardiac-specific transcription factors for their differentiation. Using conditional mutagenesis of mouse embryos, we define the hierarchy of signaling events that controls the expression of cardiac-specific transcription factors during differentiation of cardiac progenitors at embryonic day 9.0. Wnt/ß-catenin and Bmp act downstream of Notch/RBPJ at this developmental stage. Mutation of Axin2, the negative regulator of canonical Wnt signaling, enhances Wnt and Bmp4 signals and suffices to rescue the arrest of cardiac differentiation caused by loss of RBPJ. Using FACS enrichment of cardiac progenitors in RBPJ and RBPJ/Axin2 mutants, embryo cultures in the presence of the Bmp inhibitor Noggin, and by crossing a Bmp4 mutation into the RBPJ/Axin2 mutant background, we show that Wnt and Bmp4 signaling activate specific and nonoverlapping cardiac-specific genes in the cardiac progenitors: Nkx2-5, Isl1 and Baf60c are controlled by Wnt/ß-catenin, and Gata4, SRF, and Mef2c are controlled by Bmp signaling. Our study contributes to the understanding of the regulatory hierarchies of cardiac progenitor differentiation and outflow tract development and has implications for understanding and modeling heart development.

Developmental signaling in myocardial progenitor cells: a comprehensive view of Bmp- and Wnt/beta-catenin signaling.

The tight regulation of different signaling systems and the transcriptional and translational networks during embryonic development have been the focus of embryologists in recent decades. Defective developmental signaling due to genetic mutation or temporal and region-specific alteration of gene expression causes embryonic lethality or accounts for birth defects (e.g., congenital heart disease). The formation of the heart requires the coordinated integration of multiple cardiac progenitor cell populations derived from the first and second heart fields and from cardiac neural crest cells. This article summarizes what has been learned from conditional mutagenesis of Bmp pathway components and the Wnt effector, beta-catenin, in the developing heart of mice. Although Bmp signaling is required for cardiac progenitor cell specification, proliferation, and differentiation, recent studies have demonstrated distinct functions of Wnt/beta-catenin signaling at various stages of heart development.

Deciphering the function of canonical Wnt signals in development and disease: conditional loss- and gain-of-function mutations of beta-catenin in mice.

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 beta-catenin (Armadillo in Drosophila). Conditional loss- and gain-of-function mutations of beta-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 beta-catenin knockout mice, as well as the redundancy of Wnt ligands, receptors, and transcription factors. Analysis of conditional beta-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 beta-catenin loss- and gain-of-function mice.

Wnt signalling and its impact on development and cancer.

The Wnt signalling pathway is an ancient system that has been highly conserved during evolution. It has a crucial role in the embryonic development of all animal species, in the regeneration of tissues in adult organisms and in many other processes. Mutations or deregulated expression of components of the Wnt pathway can induce disease, most importantly cancer. The first gene to be identified that encodes a Wnt signalling component, Int1 (integration 1), was molecularly characterized from mouse tumour cells 25 years ago. In parallel, the homologous gene Wingless in Drosophila melanogaster, which produces developmental defects in embryos, was characterized. Since then, further components of the Wnt pathway have been identified and their epistatic relationships have been defined. This article is a Timeline of crucial discoveries about the components and functions of this essential pathway.

Distinct roles of Wnt/beta-catenin and Bmp signaling during early cardiogenesis.

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 beta-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; beta-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 beta-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/beta-catenin signaling regulates second heart-field development, and that a precise amount and/or timing of Wnt/beta-catenin signaling is required for proper heart tube formation and cardiac looping.