Heads and tails of endoderm development and adult tissue homeostasis in zebrafish

The regulatory signaling pathways crucial during embryonic development seem to play key roles in adult tissues homeostasis and are often deregulated in pathological conditions. The Wnt pathway plays a pivotal role in orchestrating cell fate decisions during embryonic development, organogenesis, and adult tissues homeostasis of endoderm-derived tissues. The canonical Wnt signaling is required at different stages of embryonic development, regulating gut patterning and organogenesis, and is instrumental for the maintenance of the intestine epithelium homeostasis in adults. Tumorigenesis arises as a disruption of the homeostatic state of a tissue. Initiation of colorectal tumorigenesis is principally associated with mutations in the APC gene, a central component of the canonical Wnt pathway. Studies of early embryonic events and molecular mechanisms regulating tissue morphogenesis and organogenesis are challenging in higher vertebrates. Due to the large clutch size, ex utero development and transparency of the embryos, zebrafish is a powerful model system to study vertebrate development. Furthermore, in recent years zebrafish has arisen as an amenable vertebrate model to study tumorigenesis in several tissues. In Chapter 3 we studied how aberrant anterior-posterior patterning in zebrafish cdx4 mutants affects foregut development. The canonical Wnt signaling pathway has an early role in establishing the anterior-posterior axis in vertebrate embryos and regulates the expression of the transcription factors from the family of Caudal-related genes, which are major determinants of posterior indentify in the embryo. Misregulation of cdx4 in zebrafish results in compromised regionalization of the gut tube, which ultimately impacts cell fate commitment and organogenesis of liver and pancreas. In Chapter 4 we investigated which transcription factors from the Tcf/Lef family acts as the main downstream effectors of the canonical Wnt pathway during the embryonic development of zebrafish. We found that different endoderm-derived tissues present a differential “Tcf code”, which ultimately mediates the tissue-specific Wnt-response in the endoderm. Tcf4 is the major effector of Wnt signaling in the intestine during zebrafish organogenesis while Tcf1 and Tcf3 are relevant during liver development. In Chapter 5 we unraveled the role of Wnt signaling in morphogenesis and adult age homeostasis of the intestinal epithelium of zebrafish. As in mouse, the Wnt signaling pathway maintains the proliferative compartment of zebrafish intestinal epithelium via Tcf4. In Chapter 6 we described a novel zebrafish gene, apc2, an orthologue of human APC2. Apc2 has been identified in several biological models and, similarly to Apc, antagonizes Wnt signaling. We found that unabated Wnt activation due to the overall reduction of Apc activity – dependent of the combined action of Apc and Apc2 – leads to neoplasia in the intestinal epithelium of adult zebrafish.