Uncovering Wnt signaling mechanisms in control of cell migration in C. elegans

Abstract

Morphogens such as Wnt proteins play a central role in embryonic patterning by providing positional information to cells in developing tissues. In recent years, it has become clear that such morphogenic gradients also contribute to the guidance of migrating cells and axons in the developing nervous system. Congenital Wnt signaling defects may result in malformations of the nervous system during development, such as spina bifida. In addition to acting as direct repulsive or attractive guidance signals, Wnt proteins can also function as permissive factors that enable cells to respond to other guidance cues. How migrating cells and growth cones interpret information from Wnt ligands to adopt a specific migratory response is, however, still largely unknown. In this thesis we have investigated in detail how migrating cells may respond to the Wnt signal. We found that the migration of the QR neuroblast and its descendants is divided in three sequential phases that are each controlled by a distinct Wnt signaling mechanism. Importantly, our results indicate that the different Wnts act permissively and that the QR cells switch between these different signaling pathways by temporally regulating the transcription of different Wnt signaling components. Furthermore, we have shown that an intricate network of interlocked negative and positive transcriptional feedback loops is required for robust activation of mab-5/Hox transcription in the QL neuroblast in response to canonical Wnt β-catenin signaling. Our modeling results demonstrate that the transcriptional feedback of Wnt signaling to both Frizzled receptors and Wnt target genes is required for robust target gene activation. Altogether, our results show that temporal transcriptional regulation and feedback of Wnt signaling components are important mechanisms to robustly and precisely regulate cell migration in response to the Wnt signal.