Evolutionarily conserved crosstalk in developmental biology

Abstract

Cellular communication is a fundamental process in animal development and homeostasis. Signaling pathways are the basis of this communication, as the transduction of external and internal cues leads to a cellular response such as cell migration, division or differentiation. Signaling pathways are often described as a unidirectional cascade, but it is important to appreciate that many signaling pathways also exhibit crosstalk, i.e. they interact with other signaling pathways to stimulate or inhibit signaling outcomes. Generally, these interactions can be classified into direct and indirect crosstalk mechanisms, where direct crosstalk refers to the convergent activity of multiple signaling pathways on the same process, whereas indirect crosstalk refers to the sequential regulation of signaling pathways. Both classes of crosstalk are common in developmental biology, but their mechanisms of action are not well understood. However, besides a deeper understanding of fundamental biological processes, knowledge on signaling pathway crosstalk is of significance for translational applications, because therapeutically interfering with a signaling pathway will affect the activity of other pathways as well. This thesis investigates the direct and indirect crosstalk of evolutionarily conserved signaling pathways in central developmental processes. In the first chapters, the role of the conserved Wnt signaling pathways during cell migration in the nematode C. elegans is explored. This reveals direct crosstalk between two Wnt signaling pathways that converge on the small GTPase CED-10/Rac to drive cell migration and highlights the dual role of the Wnt receptor CAM-1 in the migration process. Moreover, an example of indirect crosstalk in C. elegans cell migration is described as well, as the Wnt and Slit-Robo signaling pathways are functionally linked via the protein EVA-1, which is required to inhibit cell migration. This indirect crosstalk mechanism is conserved in the mammalian intestine, which is the subject studied in chapter 5. Finally, the last three chapters highlight that model system-specific research methodologies can be applied out of their original context as well. This crosstalk between research fields makes a case for the importance of interdisciplinary research.